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Originally published online as doi:10.1189/jlb.0403147 on July 22, 2003

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(Journal of Leukocyte Biology. 2004;75:39-48.)
© 2004 by Society for Leukocyte Biology

Cathelicidins, multifunctional peptides of the innate immunity

Margherita Zanetti1

Department of Biomedical Sciences and Technology, University of Udine, I-33100 Udine, and National Laboratory CIB, AREA Science Park, Padriciano 99, I-34012 Trieste

1Correspondence: Dept. Biomedical Sciences and Technology University of Udine P.le Kolbe 4, I-33100 Udine, Italy. E-mail: zanetti{at}icgeb.trieste.it


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ABSTRACT
 
Cathelicidins comprise a family of mammalian proteins containing a C-terminal cationic antimicrobial domain that becomes active after being freed from the N-terminal cathelin portion of the holoprotein. Many other members of this family have been identified since the first cathelicidin sequences were reported 10 years ago. The mature peptides generally show a wide spectrum of antimicrobial activity and, more recently, some of them have also been found to exert other biological activities. The human cathelicidin peptide LL-37 is chemotactic for neutrophils, monocytes, mast cells, and T cells; induces degranulation of mast cells; alters transcriptional responses in macrophages; stimulates wound vascularization and re-epithelialization of healing skin. The porcine PR-39 has also been involved in a variety of processes, including promotion of wound repair, induction of angiogenesis, neutrophils chemotaxis, and inhibition of the phagocyte NADPH oxidase activity, whereas the bovine BMAP-28 induces apoptosis in transformed cell lines and activated lymphocytes and may thus help with clearance of unwanted cells at inflammation sites. These multiple actions provide evidence for active participation of cathelicidin peptides in the regulation of the antimicrobial host defenses.

Key Words: cathelin • antimicrobial peptide • innate immunity • infection


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INTRODUCTION
 
Antimicrobial peptides (AMPs) are defined as such for their capacity to rapidly inactivate infectious agents [1 2 3 4 5 ]. Most AMPs act by disrupting the integrity of the microbial membranes [1 ], a feature that is accounted for by two common structural characteristics, that is, a net-positive charge and the propensity to fold into amphipathic structures, which enable these molecules to bind to negatively charged microbial surfaces and then insert into the membranes.

Mammals are equipped with diverse combinations of AMPs. These molecules are synthesized and secreted in large amounts in those tissues that are exposed to environmental microbes, such as skin and mucosal epithelia, to provide an immediate early defense against infection. The protection effected by locally synthesized peptides is reinforced by systemically derived AMPs, most of which are stored in the neutrophil granules and are released on demand at sites of microbial invasion. It is becoming increasingly manifest that many of these peptides act not only as innate microbicidal agents but can mediate a wide range of other biological effects [6 7 8 9 ].

The two major AMP families in mammals are the defensins [10 ] and another group of cationic molecules, classified as cathelicidin peptides [11 12 13 ]. Whereas the defensin structure is based on a common beta sheet core stabilized by three disulfide bonds [10 ], cathelicidin AMPs are highly heterogeneous. They range in size from 12 to 80 amino acid residues and cover a wide range of structures [14 ]. The most widespread AMPs belonging to this family are linear peptides of 23–37 amino acid residues that fold into amphipathic {alpha}-helices in environments mimicking biological membranes. Other members of this family include a number of small-sized (12–18 residues) molecules with beta-hairpin structures stabilized by one or two disulphide bonds, and a 13-residue linear peptide characterized by a high proportion of tryptophan. Yet other cathelicidin peptides are larger in size (39–80 amino acid residues) and display repetitive proline motifs forming extended polyproline-type structures. The reason all these molecules have been placed under the same cathelicidin flag, despite showing such a marked structural diversity, is that they are stored in cells in an unprocessed form in which each AMP sequence is joined to a fairly conserved N-terminal prosequence of approximately 100 residues. This is known as the "cathelin" domain (Fig. 1 ) and is a hallmark feature of the intracellular storage forms of this group of AMPs. Although the holoprotein, containing the cathelin domain followed by a varied C-terminal antimicrobial domain, is generally termed "cathelicidin," each family member has then been named individually, in some cases by using acronyms (e.g., CRAMP, BMAPs) or one-letter symbols of key amino acid residues present in the antimicrobial sequence, followed by the number of residues (e.g., LL-37, PR-39). In other cases the designation (e.g., indolicidin, protegrin, dodecapeptide) refers to specific features of the antimicrobial domains.



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  		Figure 1. Schematic representation of cathelicidin holoproteins.

The aim of this review is to provide an overview of the biology of cathelicidins with a focus on those cathelicidin peptides that, in addition to showing microbicidal properties, also exert biological activities unrelated to direct pathogen inactivation and thus have the potential to participate in various other processes connected with host defense and inflammation. In this regard, the most studied cathelicidin peptides are human LL-37, porcine PR-39, and bovine BMAP-28, and their multiple activities and molecular targets will be described here in some detail. LL-37 and BMAP-28 are representative of the {alpha}-helical type of cathelicidins that are the most widespread and are represented by at least one member in all studied mammals. PR-39 instead has a distinct structure due to an overrepresentation of proline residues, which is shared only by the bovine Bac peptides.

The cathelicidin protein family
Cathelicidins were recognized initially as constitutive components of myeloid-derived cells [13 ]. A proline-rich peptide named Bac5 played a prominent role both in the discovery of the first family members a decade ago, and in the early elucidation of their biosynthesis and maturation. Bac5 is a C-terminally amidated peptide of 43 amino acid residues, with a polycationic sequence characterized by a repeated proline motif [15 ]. This peptide was isolated from the bovine neutrophils in the late 80s, together with Bac7, a 60-residue peptide with structural features similar to Bac5, in an effort to characterize the antimicrobial repertoire of bovine leukocytes [16 ].

The trigger for the discovery of the cathelicidin family was a PCR amplification step during molecular cloning of Bac5 [17 ]. In the process of identifying the full-length cDNA, we amplified Bac5 cDNA from bovine myeloid marrow cell mRNA by pairing an oligo-dT primer with a forward oligonucleotide primer derived from a Bac5 cDNA sequence upstream from the peptide coding region. Although this sequence was thought to be unique to Bac5 cDNA, a variety of additional cDNAs were co-amplified by using these primers, and each predicted a different peptide sequence attached to a propiece that showed 75–87% sequence identity to the corresponding propiece of Bac5 [17 ]. Similarity searches of known proteins in the SwissProt database based on this propiece then revealed a pig leukocyte protein named cathelin [18 ], which shared similar size (approximately 11 kDa ) and higher-than-70% sequence identity to the propiece of the bovine peptides. These features strongly supported the argument that cathelin was the processed propiece of a yet-undiscovered pig AMP that belongs to the same family as the cattle peptides. This finding stimulated the search for novel family components with diverse AMP sequences in a variety of other mammals.

Cathelicidin family components have since been found in every mammalian species investigated (Fig. 2 ), that is, humans [19 20 21 ], monkeys [22 , 23 ], mice [24 , 25 ], rats [26 ], rabbits [27 ], guinea pigs [28 ], pigs [29 30 31 32 33 34 35 ], cattle [17 , 36 37 38 39 40 ], sheep [41 , 42 ], goats [43 ], and horses [44 ]. Each species, however, contains a different set of related genes, which reveal the presence of differential selective pressures. Eleven cathelicidin genes cluster at a CATHL@ locus on bovine chromosome 22q24 [40 , 45 ], and eight lie in close proximity on sheep chromosome 19 [46 ]. Based on the number of identified cDNAs and genes [29 30 31 32 33 34 35 , 47 48 49 ], the pig cathelicidin family is about the same size as cattle, but most peptide sequences are remarkably different; whereas the cathelin domain is highly conserved (75–80% identity) in the two species [34 ]. Humans and mice contain one typical cathelicidin each [19 , 25 ], with the corresponding genes mapped to human chromosome 3 [47 ] and mouse chromosome 9 [25 ], at regions of conserved synteny to which genes for cathelicidins have been mapped in the other species. Rabbits [50 ] and mice [51 ] also contain other cathelicidin family members that are more distantly related, but, quite surprisingly, no cathelicidin-related sequences are presently available from non-mammals. Therefore, the evolutionary history of these molecules cannot be traced with certainty. Indeed, the sequences of two pore-forming antimicrobial peptides, putatively belonging to the cathelicidin family and produced in hematopoietic cells within the intestinal submucosa of hagfish, have recently been published [52 ]. Significantly, an analysis of these sequences indicates that they could assume an {alpha}-helical structure. The discovery of cathelicidin members in hagfish would imply that ancient cathelicidin ancestors already existed 300 million years ago. However, at the time of writing, the full-length sequences of the hagfish molecules are not available, so that the association of these hagfish peptides with cathelicidin members, as based on the presence of a cathelin-like propiece, has not yet been documented conclusively.



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  		Figure 2. Phylogeny-relating mammals where cathelicidin genes have been identified. The tree was constructed by using information from references [121 122 123 ]. The designations of the respective cathelicidins are reported on top of each species. Cathelicidins of the {alpha}-helical type are in light gray boxes; those of the proline-rich type are in dark gray boxes; and those of the beta hairpin-type are in open boxes. The Trp-rich indolicidin is in hatched box.

The biosynthesis and maturation process of cathelicidins is illustrated by the results of early biochemical, immunochemical, and functional studies of the granule storage form of Bac5 in bovine myeloid cells. We found that the cathelin-containing propeptides are synthesized in the bone marrow and are stored in a myeloperoxidase-negative subset of the bovine neutrophil granules [53 ], named "large granules" [54 ]. An elastase-specific processing site, as deduced from cDNA [13 ], is present in the region that joins the cathelin domain and the AMP sequence in each propeptide. The requirement of elastase for generating active cathelicidin peptides is also supported by the rapid and complete in vitro processing of purified propeptides after addition of minute amounts of this enzyme, and by the inhibition of peptide activation in the presence of an elastase-specific inhibitor [55 ]. The granule storage forms are not harmful to microbes, as indicated by in vitro antimicrobial assays [55 ]. Unwanted intracellular processing of these molecules to active AMPs in resting neutrophils is prevented by the segregation of the propeptides and the processing enzyme to separate granule subsets, as also shown by immunoelectron microscopy of bovine neutrophils [56 ]. Biochemical and Western analyses of the secretion media of activated neutrophils provide evidence that infectious or inflammatory stimuli that result in exocytosis of the secretory and the azurophil granules convey the granule contents extracellularly (or in phagocytic vacuoles in the presence of bacteria), where the C-terminal peptides are freed from the cathelin domain by elastase-dependent proteolytic cleavage of the propeptides [55 , 56 ].

The elastase-mediated processing of cathelicidins in pig is addressed in elegant in vitro and in vivo studies by Cole et al, which highlight the contribution of cathelicidin peptides to the antimicrobial activity of porcine wound fluid [57 ]. These studies demonstrate that the maturation of protegrins (cathelicidin members) in a skin wound chamber model can be prevented by locally applying an elastase-specific inhibitor (NEI) [57 ]. The lack of mature protegrins under these conditions leads to inefficient clearance of bacteria from wound, and the addition of exogenous protegrin or excess elastase in NEI-inhibited wound fluid restores the antimicrobial activity of the fluid [57 ]. However, in other mammals or in different settings, cathelicidin peptides may be activated by different enzymes. For instance, the myeloid-derived human cationic antimicrobial protein 18 (hCAP-18) stored in the secondary granules of neutrophils [58 ] is highly susceptible to proteinase 3, a serine-proteinase of the azurophils [59 ]; whereas the epididymal-derived hCAP-18 in seminal plasma is cleaved by the prostate-derived protease gastricsin (pepsin C) when exposed to vaginal fluid at low pH [60 ].

The cathelin domain
A wealth of published data indicates that cathelicidin AMPs inactivate in vitro a variety of bacteria, fungi, and enveloped viruses with a broad overlap in specificity and significant differences in potency [14 , 61 , 62 ]. Evidence is mounting to firmly implicate these peptides in in vivo protection against infection [see below]. Conversely, a limited number of papers are concerned with the function of the cathelin propiece, and the biological role of this evolutionarily conserved domain is still a matter for debate. According to a recent report [63 ], the cathelin domain of the human cathelicidin hCAP-18 is endowed with antimicrobial properties after being released by proteolytic processing of the holoprotein. This observation would imply that proteolytic cleavage of hCAP-18 generates two distinct AMPs, LL-37 and cathelin. Based on in vitro assays, the recombinant cathelin (approximately 11 kDa) is active at 16–32 µM against bacterial strains that are resistant to LL-37, so that the two proteins appear to exert complementary antibiotic activities [63 ]. The mechanism of the antimicrobial activity of cathelin is unlikely to resemble that of cationic AMPs, since this portion of the holoprotein has no net-positive charge and its structure in no way resembles that of known AMPs. Cathelin shows an intriguing sequential and structural similarity to members of the cystatin superfamily of cysteine proteinase inhibitors, at both the protein [18 , 64 ] and gene [40 , 65 ] levels. The structural similarities are highlighted in the recently published X-ray structure of the cathelin motif of porcine protegrin-3, which shows a fold homologous to cystatins [66 ]. The common evolutionary relatedness of cathelicidin and cystatin family members is supported further by the inhibitory effects exerted by bovine cathelicidins [64 , 67 ], or of their cathelin domain [63 ], on the in vitro activity of cathepsin L, a cysteine proteinase that can contribute to tissue injury. However, the Ki values of cathelicidins generally are in the 10-7 M range [64 , 67 ], which are considerably higher than those of cystatins. This may render the physiological significance of this effect questionable and leaves open the possibility of still other significant roles that may have resulted in strong pressure for conservation of this sequence. It is interesting to observe in this regard that the human cathelicidin peptide LL-37 is detected primarily as the uncleaved holoprotein hCAP-18 (Fig. 3 ) in many settings, for example, wound and blister fluids [68 ], phagocytic vacuoles [59 ], psoriatic skin [69 ], seminal plasma [70 ], and associates to plasma lipoproteins in the hCAP-18 form [71 , 72 ]. A possible explanation for the widespread presence of uncleaved hCAP-18 is that the cathelin domain protects the peptide from proteolytic degradation in protease-rich media, although both the mature LL-37 and the holoprotein have been shown to be degraded in vitro and ex vivo in human wound fluid by elastase-producing P. aeruginosa [73 ].



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  		Figure 3. Alignment of the amino acid sequences of Bac5 and BMAP-28 as deduced from cattle, of PR-39 from pig, and of hCAP-18 from human myeloid mRNA. An arrow indicates the predicted cleavage site for signal peptidase. The regions corresponding to the antimicrobial domain are in bold. Dashes denote residues identical to those in the sequence of Bac5. Compared with the deduced sequences, the sequences of BMAP-28 and Bac5 peptides isolated from neutrophils (not shown) are C-terminally amidated as a result of post-translational modification, with loss of the C-terminal G in the case of BMAP-28 and of the C-terminal (GRR) sequence in the case of Bac5.

The human cathelicidin hCAP-18/LL-37
Among the known cathelicidins, those carrying a C-terminal peptide of the {alpha}-helical type are present in every mammal thus far investigated and are the lone cathelicidin type identified in some species, for example, humans (hCAP-18/LL-37), rabbits (CAP18), mice (CRAMP), and rats (rCRAMP) (Fig. 2) . Its widespread presence would suggest that the {alpha}-helical cathelicidin type is the progenitor molecule from which this family differentially expanded in mammals by repeated gene duplications and divergence of the peptide coding sequence, which gives rise to a variety of gene family members in some species (Fig. 2) . Although initially recognized as neutrophil-specific constituents, the {alpha}-helical-type cathelicidins are distributed widely in cells and tissues. Particularly, hCAP-18/LL-37 (Fig. 3) , which liberates an {alpha}-helical peptide (LL-37) of 37 amino acid residues. hCAP-18/LL-37 has been shown by RT-PCR, in situ hybridization and immunohistochemical analysis to be produced in various blood cells populations, that is, NK, {gamma}{delta}T cells, B cells, monocytes [74 ], and mast cells [75 ], in addition to immature neutrophils [58 ]. The hCAP-18 gene is also expressed in the squamous epithelia of the airways, mouth, tongue, esophagus, intestine, cervix, and vagina [76 , 77 ]; in sweat [78 ] and salivary [79 ] glands; in epididymis and testis [19 , 80 , 81 ]. The polypeptide is secreted in human wound [68 ], sweat [78 ], and airway surface [77 ] fluids and is especially abundant in seminal plasma [70 ], where it may provide a sterile environment during fertilization. Several lines of evidence suggest that LL-37 plays an early defensive role at these sites. For instance, the hCAP-18 gene is up-regulated in skin in response to cutaneous infection or injury [82 ] and in inflammatory disorders of the skin, such as psoriasis [69 , 83 ]. In contrast, low expression of both hCAP-18 and human beta defensin-2 (HBD-2) genes has been detected in skin lesions from patients with atopic dermatitis. The ensuing deficiency of LL-37 and HBD-2 may provide an explanation for the increased susceptibility of patients with atopic dermatitis to skin infection, compared with patients with psoriasis [69 ]. A role of LL-37 in prevention of oral bacterial infections is supported by the observation that LL-37 deficiency in neutrophils from patients with morbus Kostmann, a severe congenital neutropenia, correlates with the occurrence of chronic periodontal disease in these patients [84 ]. Also in favor of the involvement of LL-37 in prevention of bacterial invasion is the finding that hCAP-18 is down-regulated in gut biopsies of patients with Shigella infections, as well as Shigella-infected monocyte and epithelial-derived cell lines [85 ]. The results of this study suggest that antimicrobial peptide-encoding genes can be repressed by pathogenic microbes as part of a strategy aimed to circumvent immune defenses, resulting in increased virulence. Indirect evidence that endogenous expression of LL-37 protects from skin infections comes from the demonstration that mice null for the CRAMP cathelicidin gene are much more susceptible to skin infection by group A Streptococcus than wild-type mice are [86 ]. In this respect, it is worth noting that CRAMP and LL-37 are structurally similar and, in addition, both are induced in the skin following skin injury and both are active against group A Streptococcus [82 ]. The role of LL-37 in host defense against microbes has also been investigated by using a genetic approach based on adenoviral-mediated hCAP-18 gene transfer into respiratory epithelia [87 , 88 ]. When recombinant hCAP-18 is overexpressed in a human bronchial xenograft model, it reverses the cystic fibrosis-specific bacterial killing defect. This finding supports the hypothesis that a deficient activity of AMPs contributes to lung disease in cystic fibrosis [87 ]. In keeping with these results, transfer of hCAP-18/LL-37 gene into mouse airways results in a decreased bacterial load as well as decreased inflammatory response in P. aeruginosa-infected mice [88 ]. Furthermore, systemic overexpression of this gene protects D-GalN-sensitized mice injected with LPS or E. coli from septic death [88 ], which suggests that LL-37 not only contributes to clearance of bacteria, it also offers systemic protection against the detrimental effects of massive microbial invasion. This action may depend largely on the LPS-binding and LPS-neutralizing properties of LL-37 [89 90 91 92 ]. Some cathelicidin AMPs bind free LPS with high affinity [93 , 94 ], and both the human and rabbit peptides have been shown to inhibit LPS-induced cellular responses, such as release of TNF-{alpha}, nitric oxide, and tissue factor [89 , 93 , 95 ], whereas further in vitro studies have assessed the ability of LL-37 to inhibit macrophage activation by other bacterial components (lipoteichoic acid and noncapped lipoarabinomannan) in addition to LPS [92 ].

The discovery of additional novel activities unrelated to direct pathogen inactivation may disclose a far more complex role of LL-37 in host defense than earlier suspected. LL-37 has chemotactic effects in vitro, inducing selective migration of human peripheral blood monocytes, neutrophils, and CD4 T cells [74 , 96 ] with a dose-dependent, bell-shaped response, and optimal concentrations that range from 10-7 to 10-5 M. The chemotactic activity is not affected by serum [96 ], at serum concentrations that are known to inhibit the in vitro antimicrobial effects of LL-37 [97 ]. This suggests that the two activities are mediated by different mechanisms. This hypothesis is further supported by the finding that the chemotactic activity of LL-37 depends on binding to formyl peptide receptor-like 1 (FPRL1, see ref. [98 ] for an overview of the FPR family), as indicated by the identification of an agonistic ligand specific for this receptor in monocytes, and by the ability of LL-37 to chemoattract cells that express FPRL1 gene, or cells transfected for FPRL1 gene expression [96 ]. LL-37 would thus contribute to immune responses by recruiting inflammatory and immune cells that express functional FPRL1. LL-37 is also chemotactic for rat peritoneal mast cells (MCs), seemingly through different receptor(s), as suggested by a competitive binding assay by using a FPRL1-specific agonist [99 ], with an optimal concentration of 5 µg/ml. In addition, LL-37 induces histamine release and intracellular Ca2+ mobilization in these cells [100 ]. MCs are among the first inflammatory cells to encounter invading pathogens, which are preferentially located at host/environment interface. These cells can initiate site-specific inflammation by phagocytosing and killing opsonized bacteria and through neutrophil recruitment [101 ]. It is interesting to note in this respect that MCs are not only a target but are also a source of LL-37, as shown by immunohistochemical analysis of dermis [75 ], although the peptide may not be secreted extracellularly [75 ]. As a cellular component of MCs, LL-37 may contribute to the intraphagolysosome microbial killing [75 ]. In addition, because it is synthesized and released at inflammatory sites by both resident and inflammatory cells, this peptide may form chemotactic gradients and help with MC recruitment. Furthermore, LL-37-induced MC degranulation would lead to release of inflammatory mediators, including neutrophil chemoattractants and histamine [100 ], which would increase vascular permeabilization thus favoring neutrophil infiltration of inflamed tissues. In this scenario, LL-37 may play a role in infected epithelia as a direct antimicrobial effector and as a mediator of positive amplification loops of innate and immune responses, by participating in the recruitment of more and additional types of leukocytes.

This picture may be enriched further by the suggested ability of LL-37 to alter transcriptional responses, as assessed by gene array-based studies [92 ]. According to these studies, LL-37 at 50–100 µg/ml regulates a number of genes in the murine macrophage cell line RAW 264.7 and in the human epithelial cell line A549, some of which are anti-inflammatory and some have pro-inflammatory roles. Among the genes that are predicted to be up-regulated are chemokine and chemokine receptor genes [92 ], which suggests that direct migration of immune cells, and possibly other cellular responses, may be induced by this peptide through modulation of gene expression in target cells. More in-depth studies, however, are required to identify the interacting molecule in these cells, to elucidate the regulation pathway involved, and to explain the biological significance of this activity. The in vitro concentrations required are high, compared with those observed for other in vitro activities of LL-37. However, the fact that high concentrations of hCAP-18 have been detected in seminal plasma (range of 41.8 to 142.8 µg/ml from 10 healthy donors [80 ]) compared with the plasma lipoprotein-associated polypeptide (approximately 1.2 µg/ml plasma) [102 ], suggests that it could be present in sufficiently large amounts in some in vivo settings.

In addition to its capability to augment host defenses, LL-37 appears to play a role in repair of damaged tissue and wound closure, by promoting wound neovascularization [103 ] and re-epithelialization of healing skin [104 ]. High levels of LL-37 expression are detected in human skin upon wounding, both in vivo [82 , 104 ] and in a non-inflammatory ex vivo wound healing model composed of organ-cultured human skin [104 ]. Evidence for the involvement of this peptide in re-epithelialization of healing skin epithelium is provided by the ability of LL-37-specific antibodies to inhibit this process in the ex vivo wound healing model [104 ]. The precise mechanism of this activity has not been clarified, but lack of immunoreactivity for the proliferation marker Ki67 in the LL-37 antibody-inhibited wound argues for a role of the peptide in the proliferative step [104 ]. In this context, LL-37 may also induce cutaneous wound vascularization, based on the finding that application of exogenous LL-37 results in angiogenesis both in the chorioallantoic membrane assay and in a rabbit hind-limb model of ischemia [103 ]. The ability of this peptide to stimulate proliferation of cultured HUVECs and to cause endothelial sprouting from hamster aortic rings strongly suggests that the angiogenic effect depends on direct activation of endothelial cells [103 ], a process that appears to be mediated by interaction of LL-37 with FPRL1 expressed on endothelial cells [103 ].

BMAP and Bac peptides in cattle
In contrast with a single member of this family being present in humans, a variety of cathelicidin peptides are found in cattle. Their marked structural diversity suggests distinct functional capabilities of these molecules and a possibly diversified biological role in host defense. In this regard, it is worth comparing the in vitro antimicrobial activity of {alpha}-helical (BMAP-27 and BMAP-28, acronym for "Bovine Myeloid Antimicrobial Peptides"; [39 ]), and proline-rich (Bac5 and Bac7) bovine peptides [15 , 16 ]. We have shown that BMAPs rapidly permeabilize and kill in vitro a wide range of bacteria and fungi in the low micromolar and submicromolar range of peptide concentrations [39 ], whereas under the same experimental conditions, the proline-rich type peptides almost exclusively target gram-negative bacteria [16 ]. BMAPs are hemolytic in vitro at concentrations that are approximately tenfold higher than those microbicidal, and assays based on cellular uptake of propidium iodide and release of the cytoplasmic enzyme LDH indicate that they are toxic to cultured blood cells and to blood cell- [105 ], epithelial-, and fibroblast-derived (unpublished data) cell lines, with a higher susceptibility of hematopoietic tumor cell lines versus normal leukocytes, and of in vitro activated versus resting human lymphocytes [105 ]. Conversely, under the same experimental conditions, the proline-rich Bac peptides are not lytic to mammalian cells (unpublished data).

The cytotoxicity induced by BMAP-28 (sequence in Fig. 3 ) has been investigated by flow cytometry and confocal microscopy of activated human lymphocytes and hematopoietic and fibroblast-derived ( [105 , 106 ] and unpublished data) cell lines. This molecule causes cell membrane permeabilization, as indicated by propidium iodide uptake, with early Ca2+ influx [105 ], and this event is followed by apoptosis in a variable proportion of the cells, as determined by analysis of DNA laddering [105 ], by scoring picnotic nuclei, and by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (unpublished data). The apoptotic effects likely depend on peptide-mediated induction of the mitochondrial permeability transition pore (MPTP), as suggested by the ability of BMAP-28 to target mitochondrial membranes in both single cells and isolated mitocondria, and to induce cyclosporine-inhibitable decrease of the inner mitochondrial membrane potential and release of cytochrome c [106 ].

Whereas the higher toxicity of BMAP-28 towards transformed versus normal cells underscores the potential contribution of neutrophils in causing active death of tumor cells, the susceptibility of proliferating versus resting lymphocytes may implicate this peptide in the resolution of inflammation. The concentration of BMAP-28 secreted at inflammation sites likely correlates with the number of accumulating neutrophils. Early in the course of inflammation, BMAP-28 would be present in the low amounts required for pathogen inactivation, whereas, with amplified neutrophil recruitment, the local peptide concentration may gradually increase to the extent required to cause death of activated (and/or possibly, infected) host cells. Our in vitro studies indicate that a substantial amount of BMAP-28-susceptible cells die by apoptosis, which suggests that this peptide could contribute via this mechanism to prevent excessive tissue injury caused by release of enzymes and other toxic cellular components.

The toxicity of BMAPs is reflected by the fact that their abundance is relatively low in neutrophils, as revealed by Northern and Western analyses of immature and mature neutrophils (unpublished observations), as compared with Bac5 and Bac7, which altogether comprise 4% of total neutrophil proteins, as based on immunochemical quantification of the storage forms [56 ]. Conversely, RT-PCR analysis of bovine tissues points to a wider tissue distribution of BMAP peptides (unpublished data) compared with the myeloid-restricted tissue distribution of Bac5 [107 ]. That distinct members of this gene family may be differentially expressed and regulated in cattle is also supported by expression studies of Bac5 (Fig. 3) in neutrophils. Like the other bovine cathelicidins, Bac5 is actively synthesized in bone marrow immature neutrophils, and its biosynthesis is turned off in fully differentiated neutrophils [107 ]. Yet, we have detected high levels of expression of this gene in inflammatory neutrophils infiltrates by in situ hybridization of lung samples from animals with airways infections, which suggests that the expression of this gene can be re-induced in mature neutrophils [107 ]. Accordingly, stimulation of cultured peripheral neutrophils with bacterial lysates or bacterial lipopolysaccharide results in up-regulation of Bac5 gene expression, as revealed by RT-PCR and Northern blotting, and in extracellular release of the newly synthesized polypeptide [107 ]. No BMAP-related transcripts are detected by RT-PCR in neutrophils under these conditions. Notably, Bac5 mRNA is present at detectable levels in these cells only 12–20 h after cell activation. This delayed induction time could be consistent with the need to maintain a prolonged antimicrobial defense at sites of infection, but it could also suggest a role of the newly synthesized Bac5 in activities unrelated to direct bacterial killing. The overall structural similarity of Bac5 to PR-39 (Fig. 3) , a multifunctional, proline-rich, porcine cathelicidin peptide of 39 amino acid residues [29 , 108 ], might support the latter hypothesis.

PR-39, a porcine cathelicidin peptide
PR-39 was initially characterized as an antibacterial factor [108 ] and was later suggested to potentially affect a number of biological responses by acting as a molecular signal. The first evidence for a signaling role of PR-39 was the isolation of a factor capable of inducing syndecan-1 and -4 in cultured mesenchimal cells from wound fluid [109 ]. The syndecan-inducing factor turned out to be identical to PR-39, which likely is released in wound fluid by recruited neutrophils. Syndecans are cell-surface heparan sulfate proteoglycans that are involved in biological processes, such as regulation of blood coagulation, cell adhesion, and wound repair [110 ]. Syndecan-1 expression in mesenchymal cells is increased during wound repair, which causes the cells to become more responsive to numerous effector molecules, including heparin-binding growth factors such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and transforming growth factor ß (TGF-ß) [110 ]. Syndecan members are thought to contribute to wound repair by regulating cell proliferation and migration in response to these effectors. The syndecan-inducing activity of PR-39 suggests that the peptide may function as a signaling molecule in wound repair.

The mechanism by which PR-39 can alter mammalian gene expression has been investigated by using PR-39(15), a 15-residue, biologically functional fragment [111 ]. This molecule rapidly enters cells without causing membrane damage and selectively binds cytosolic proteins containing Src homology 3 (SH3) domains, as predicted by the presence of SH3-binding motifs in its sequence, including a RxxPxxP motif at the N-terminus [111 ]. In vitro experiments indicate that PR-39(15) binds various recombinant and native SH3-containing proteins, including p130Cas [111 ], an adapter protein that has been implicated in numerous signaling pathways [112 ], and induces a redistribution of this protein from cytosol to cytoskeleton in endothelial cells, leading to activation of p130Cas-associated signaling pathways. Further SH3-containing target molecules of PR-39, including the regulatory subunit of PI3-kinase, PI3-kinase p85{alpha}, have been identified by transfecting the PR-39 gene in NIH/3T3 fibroblasts transformed with human activated k-ras [113 ].

Other in vitro studies suggest that PR-39 is chemotactic for neutrophils at 0.5–2 µM [114 ], although the cellular receptor for this activity has not been identified and inhibits the phagocyte NADPH oxidase activity at slightly higher concentrations [115 ], which points to the involvement of this peptide in the regulation of acute inflammation. The NADPH oxidase catalyzes the reduction of molecular oxygen to superoxide anion, leading to production of reactive oxygen species. These are essential components of early host defense, although their toxicity can cause significant tissue injury during inflammation [116 ]. PR-39 inhibits NADPH oxidase by blocking assembly via interaction with SH3 domains, which are present in the cytosolic subunit p47phox and are responsible for its interaction with the membrane component p22phox [115 ].

PR-39 is also an inducer of angiogenesis in cell culture and in vivo in mouse myocardium [117 ]. This effect appears to be mediated by the inhibition of ubiquitin-proteasome-dependent degradation of the hypoxia-inducible factor HIF-1{alpha} [117 ], which up-regulates the expression of angiogenesis-related genes, including vascular endothelial growth factor (VEGF) [118 ], and is therefore distinct from the one described for LL-37 [103 ]. Actually, this activity of PR-39 would provide a link between the two major stimulants of angiogenesis, inflammation, and hypoxia, in that a peptide released during the inflammatory response promotes an increased concentration of HIF-1{alpha}, which mediates the hypoxia effects.

Furthermore, PR-39 can bind the {alpha}7 subunit of the 26S proteasome, as determined in a yeast two-hybrid screening of a mouse cDNA library, and can block the ubiquitin-proteasome pathway-mediated degradation of the NF-{kappa}B inhibitor I{kappa}B{alpha} without affecting overall proteasome activity [119 ]. The inhibition of proteasome-dependent degradation of IkB{alpha} results in I{kappa}B accumulation in cells stably expressing PR-39, and this in turn abolishes induction of NF-{kappa}B-dependent gene expression both in vitro and in in vivo mouse models of acute pancreatitis and myocardial infarction [119 ]. A functional consequence of PR-39-mediated inhibition of NF-{kappa}B activity is a decrease in the expression of the endothelial adhesion proteins VCAM-1 and ICAM-1, both in cell culture and in the setting of acute myocardial infarction in transgenic mice expressing PR-39 in cardiac myocytes. This might explain, at least in part, the reduced adherence of polymorphonuclear cells to coronary vascular endothelium and the reduced injury observed in mouse and rat models of myocardial ischemia-reperfusion after treatment with PR-39 [120 ]. It is unclear whether inhibition of IkB degradation is also responsible for the inhibition of HIF-1{alpha} degradation.

Collectively, these studies suggest that PR-39 may have a wide range of effects in different cell types. The ability of PR-39 to bind SH3 domain-containing proteins may reconcile all these findings and provide an explanation for the capacity of PR-39 to mediate such a variety of effects. However, the relevance of these activities in (patho)physiological settings remains to be established and, in this respect, an intriguing observation that may limit the general biological significance of these effects is the apparent absence of PR-39 homologues in humans.


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Conclusions
 
For several years after the discovery of mammalian AMPs, speculation about the biological role of these peptides was mostly limited to their direct antimicrobial activity, based on their ability to interact with microbial components. The subsequent finding that various defensins and some cathelicidin peptides can also interact with host cells and trigger a variety of activities unrelated to direct microbial killing [6 7 8 9 ] has changed the way we look at these molecules. Our perception has changed from that of considering them isolated soldiers in a first-line trench of innate immunity to effector molecules highly integrated with other mediators of host defense, helping to orchestrate a variety of inflammatory and immune responses, and participating in the cross-talk between innate and adaptive immunity.

It is remarkable, considering their small size (the cathelicidin peptides LL-37 and PR-39, for instance, are, respectively, 37 and 39 amino acid residues) and their relatively simple structures, that these peptides could contain all the necessary information to exerting multiple and diverse actions, which in most cases require specific molecular interaction. It is also remarkable that a number of overlapping activities are displayed by peptides that are structurally quite diverse. In this respect, LL-37 ({alpha}-helical) and PR-39 (extended proline-rich) combine features of AMPs, chemoattractants, and growth factors with defensin members (ß-sheets) [8 , 9 ]. This underlines what appears to be a characteristic feature of innate immunity: an apparent redundancy in the activities of innate effector molecules that has entailed a substantial degree of functional convergence on processes that are crucial to an efficient protection of the host against infection, that is, rapid clearance of bacteria, mobilization of immune responses, and repair of damaged barrier epithelia.

Future research should aim to better clarify the molecular mechanisms underlying all these activities but, also important, to assess how these activities impact on in vivo settings. In this respect, the experimental conditions used may not adequately reflect the complexity of the inflammatory sites where AMPs are secreted and the fact that the recruitment of different cell types makes this microenvironment crowded with molecules, some of which may interfere with the AMP activities in terms of synergy, competition, or inhibition.

Additional studies should aim to identify novel activities also by other cathelicidin peptides. We are encouraged by the fact that each new piece in the puzzle seems to fall into place in a fascinating picture, although it is a far more ample, complex, and relevant picture than we ever suspected a few years ago.


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ACKNOWLEDGEMENTS
 
I am grateful to A. Tossi, from the Dept. Biochemistry of the University of Trieste, for critical reading of the manuscript, and to L. Tomasinsig, from the Dept. Biomedical Sciences and Technology of the University of Udine, for help with preparing the manuscript. Work conducted in the author laboratory was supported by grants from the Italian Ministry for University and Research (P.R.I.N. Cofin. 2000 and 2002), CNR (Agenzia 2000), and Regione FVG.

Received April 10, 2003; revised June 9, 2003; accepted June 20, 2003.


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REFERENCES
 
    1
  1. Zasloff, M. (2002) Antimicrobial peptides of multicellular organisms Nature 415,389-395[CrossRef][Medline]
    2. 2
  2. Ganz, T. (2002) Antimicrobial polypeptides in host defense of the respiratory tract J. Clin. Invest. 109,693-697[CrossRef][Medline]
    3. 3
  3. Hancock, R. E., Diamond, G. (2000) The role of cationic antimicrobial peptides in innate host defences Trends Microbiol. 8,402-410[CrossRef][Medline]
    4. 4
  4. Lehrer, R. I., Ganz, T. (1999) Antimicrobial peptides in mammalian and insect host defence Curr. Opin. Immunol. 11,23-27[CrossRef][Medline]
    5. 5
  5. Boman, H. G. (1998) Gene-encoded peptide antibiotics and the concept of innate immunity: an update review Scand. J. Immunol. 48,15-25[CrossRef][Medline]
    6. 6
  6. Yang, D., Biragyn, A., Kwak, L. W., Oppenheim, J. J. (2002) Mammalian defensins in immunity: more than just microbicidal Trends Immunol. 23,291-296[CrossRef][Medline]
    7. 7
  7. Yang, D., Chertov, O., Oppenheim, J. J. (2001) The role of mammalian antimicrobial peptides and proteins in awakening of innate host defenses and adaptive immunity Cell. Mol. Life Sci. 58,978-989[CrossRef][Medline]
    8. 8
  8. Yang, D., Chertov, O., Oppenheim, J. J. (2001) Participation of mammalian defensins and cathelicidins in anti-microbial immunity: receptors and activities of human defensins and cathelicidin (LL-37) J. Leukoc. Biol. 69,691-697[Abstract/Free Full Text]
    9. 9
  9. Scott, M. G., Hancock, R. E. (2000) Cationic antimicrobial peptides and their multifunctional role in the immune system Crit. Rev. Immunol. 20,407-431[Medline]
    10. 10
  10. Lehrer, R. I., Ganz, T. (2002) Defensins of vertebrate animals Curr. Opin. Immunol. 14,96-102[CrossRef][Medline]
    11. 11
  11. Lehrer, R. I., Ganz, T. (2002) Cathelicidins: a family of endogenous antimicrobial peptides Curr. Opin. Hematol. 9,18-22[CrossRef][Medline]
    12. 12
  12. Zaiou, M., Gallo, R. L. (2002) Cathelicidins, essential gene-encoded mammalian antibiotics J. Mol. Med. 80,549-561[CrossRef][Medline]
    13. 13
  13. Zanetti, M., Gennaro, R., Romeo, D. (1995) Cathelicidins: a novel protein family with a common proregion and a variable C-terminal antimicrobial domain FEBS Lett. 374,1-5[CrossRef][Medline]
    14. 14
  14. Gennaro, R., Zanetti, M. (2000) Structural features and biological activities of the cathelicidin-derived antimicrobial peptides Biopolymers 55,31-49[CrossRef][Medline]
    15. 15
  15. Frank, R. W., Gennaro, R., Schneider, K., Przybylski, M., Romeo, D. (1990) Amino acid sequences of two proline-rich bactenecins. Antimicrobial peptides of bovine neutrophils J. Biol. Chem. 265,18871-18874[Abstract/Free Full Text]
    16. 16
  16. Gennaro, R., Skerlavaj, B., Romeo, D. (1989) Purification, composition and activity of two bactenecins, antibacterial peptides of bovine neutrophils Infect. Immun. 57,3142-3146[Abstract/Free Full Text]
    17. 17
  17. Zanetti, M., Del Sal, G., Storici, P., Schneider, C., Romeo, D. (1993) The cDNA sequence of the neutrophil antibiotic Bac5 predicts a pro-sequence homologous to a cysteine proteinase inhibitor, that is common to other neutrophil antibiotics J. Biol. Chem. 268,522-526[Abstract/Free Full Text]
    18. 18
  18. Ritonja, A., Kopitar, M., Jerala, R., Turk, V. (1989) Primary structure of a new cysteine proteinase inhibitor from pig leucocytes FEBS Lett. 255,211-214[CrossRef][Medline]
    19. 19
  19. Agerberth, B., Gunne, H., Oderberg, J., Kogner, P., Boman, H. G., Gudmundsson, G. H. (1995) FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis Proc. Natl. Acad. Sci. USA 92,195-199[Abstract/Free Full Text]
    20. 20
  20. Cowland, J. B., Johnsen, A. H., Borregaard, N. (1995) hCAP-18, a cathelin/pro-bactenecin-like protein of human neutrophil specific granules FEBS Lett. 368,173-176[CrossRef][Medline]
    21. 21
  21. Larrick, J. W., Hirata, M., Balint, R. F., Lee, J., Zhong, J., Wright, S. C. (1995) Human CAP18: a novel antimicrobial lipopolysaccharide-binding protein Infect. Immun. 63,1291-1297[Abstract/Free Full Text]
    22. 22
  22. Zhao, C., Nguyen, T., Boo, L. M., Hong, T., Espiritu, C., Orlov, D., Wang, W., Waring, A., Lehrer, R. I. (2001) RL-37, an alpha-helical antimicrobial peptide of the rhesus monkey Antimicrob. Agents Chemother. 45,2695-2702[Abstract/Free Full Text]
    23. 23
  23. Bals, R., Lang, C., Weiner, D. J., Vogelmeier, C., Welsch, U., Wilson, J. M. (2001) Rhesus monkey (Macaca mulatta) mucosal antimicrobial peptides are close homologues of human molecules Clin. Diagn. Lab. Immunol. 8,370-375[Abstract/Free Full Text]
    24. 24
  24. Popsueva, A. E., Zinovjeva, M. V., Visser, J. W. M., Zijlmans, J. M. J. M., Fibbe, W. E., Belyavsky, A. V. (1996) A novel murine cathelin-like protein expressed in bone marrow FEBS Lett. 391,5-8[CrossRef][Medline]
    25. 25
  25. Gallo, R. L., Kim, K. J., Bernfield, M., Kozak, C. A., Zanetti, M., Merluzzi, L., Gennaro, R. (1997) Identification of CRAMP, a cathelin related antimicrobial peptide expressed in the embryonic and adult mouse J. Biol. Chem. 272,13088-13093[Abstract/Free Full Text]
    26. 26
  26. Termen, S., Tollin, M., Olsson, B., Svenberg, T., Agerberth, B., Gudmundsson, G. H. (2003) Phylogeny, processing and expression of the rat cathelicidin rCRAMP: a model for innate antimicrobial peptides Cell. Mol. Life Sci. 60,536-549[CrossRef][Medline]
    27. 27
  27. Larrick, J. W., Morgan, J. G., Palings, I., Hirata, M., Yen, M. H. (1991) Complementary DNA sequence of rabbit CAP18-a unique lipopolysaccharide binding protein Biochem. Biophys. Res. Commun. 179,170-175[CrossRef][Medline]
    28. 28
  28. Nagaoka, I., Tsutsumi-Ishii, Y., Yomogida, S., Yamashita, T. J. (1997) Isolation of cDNA encoding guinea pig neutrophil cationic antibacterial polypeptide of 11 kDa (CAP11) and evaluation of CAP11 mRNA expression during neutrophil maturation J. Biol. Chem. 272,22742-22750[Abstract/Free Full Text]
    29. 29
  29. Storici, P., Zanetti, M. (1993) A cDNA derived from pig bone marrow cells predicts a sequence identical to the intestinal antibacterial peptide PR-39 Biochem. Biophys. Res. Commun. 196,1058-1065[CrossRef][Medline]
    30. 30
  30. Storici, P., Zanetti, M. (1993) A novel cDNA sequence encoding a pig leukocyte antimicrobial peptide with a cathelin-like pro-sequence Biochem. Biophys. Res. Commun. 196,1363-1368[CrossRef][Medline]
    31. 31
  31. Zhao, C., Liu, L., Lehrer, R. I. (1994) Identification of a new member of the protegrin family by cDNA cloning FEBS Lett. 346,285-288[CrossRef][Medline]
    32. 32
  32. Storici, P., Scocchi, M., Tossi, A., Gennaro, R., Zanetti, M. (1994) Chemical synthesis and biological activity of a novel antibacterial peptide deduced from a pig myeloid cDNA FEBS Lett. 337,303-307[CrossRef][Medline]
    33. 33
  33. Zanetti, M., Storici, P., Tossi, A., Scocchi, M., Gennaro, R. (1994) Molecular cloning and chemical synthesis of a novel antibacterial peptide derived from pig myeloid cells J. Biol. Chem. 269,7855-7858[Abstract/Free Full Text]
    34. 34
  34. Tossi, A., Scocchi, M., Zanetti, M., Storici, P., Gennaro, R. (1995) PMAP-37, a novel pig myeloid antibacterial peptide Eur. J. Biochem. 228,941-946[Medline]
    35. 35
  35. Strukelj, B., Pungercar, J., Kopitar, G., Renko, M., Lenarcic, B., Berbic, S., Turk, V. (1995) Molecular cloning and identification of a novel porcine cathelin-like antibacterial peptide precursor Biol. Chem. Hoppe Seyler 376,507-510[Medline]
    36. 36
  36. Del Sal, G., Storici, P., Schneider, C., Romeo, D., Zanetti, M. (1992) cDNA cloning of the neutrophil bactericidal peptide indolicidin Biochem. Biophys. Res. Commun. 187,467-472[CrossRef][Medline]
    37. 37
  37. Storici, P., Del Sal, G., Schneider, C., Zanetti, M. (1992) cDNA sequence analysis of an antibiotic dodecapeptide from neutrophils FEBS Lett. 314,187-190[CrossRef][Medline]
    38. 38
  38. Scocchi, M., Romeo, D., Zanetti, M. (1994) Molecular cloning of Bac7, a proline- and arginine-rich antimicrobial peptide from bovine neutrophils FEBS Lett. 352,197-200[CrossRef][Medline]
    39. 39
  39. Skerlavaj, B., Gennaro, R., Bagella, L., Merluzzi, L., Risso, A., Zanetti, M. (1996) Biological characterization of two novel cathelicidin-derived peptides and identification of structural requirements for their antimicrobial and cell lytic activities J. Biol. Chem. 271,28375-28381[Abstract/Free Full Text]
    40. 40
  40. Scocchi, M., Wang, S., Zanetti, M. (1997) Structural organization of the bovine cathelicidin gene family and identification of a novel member FEBS Lett. 417,311-315[CrossRef][Medline]
    41. 41
  41. Bagella, L., Scocchi, M., Zanetti, M. (1995) cDNA sequences of three sheep myeloid cathelicidins FEBS Lett. 376,225-228[CrossRef][Medline]
    42. 42
  42. Mahoney, M. M., Lee, A. Y., Brezinski-Caliguri, D. J., Huttner, K. M. (1995) Molecular analysis of the sheep cathelin family reveals a novel antimicrobial peptide FEBS Lett. 377,519-522[CrossRef][Medline]
    43. 43
  43. Shamova, O., Brogden, K. A., Zhao, C., Nguyen, T., Kokryakov, V. N., Lehrer, R. I. (1999) Purification and properties of proline-rich antimicrobial peptides from sheep and goat leukocytes Infect. Immun. 67,4106-4111[Abstract/Free Full Text]
    44. 44
  44. Scocchi, M., Bontempo, D., Boscolo, S., Tomasinsig, L., Giulotto, E., Zanetti, M. (1999) Novel cathelicidins in horse leukocytes FEBS Lett. 457,459-464[CrossRef][Medline]
    45. 45
  45. Castiglioni, B., Scocchi, M., Zanetti, M., Ferretti, L. (1996) Six antimicrobial peptide genes of the cathelicidin family map to bovine chromosome 22q24 by fluorescence in situ hybridization Cytogenet. Cell. Genet. 75,240-242[Medline]
    46. 46
  46. Huttner, K. M., Lambeth, M. R., Burkin, H. R., Burkin, D. J., Broad, T. E. (1998) Localization and genomic organization of sheep antimicrobial peptide genes Gene 206,85-91[CrossRef][Medline]
    47. 47
  47. Gudmundsson, G. H., Magnusson, K. P., Chowdhary, B. P., Johansson, M., Andersson, L., Boman, H. G. (1995) Structure of the gene for porcine peptide antibiotic PR-39, a cathelin gene family member: comparative mapping of the locus for the human peptide antibiotic FALL-39 Proc. Natl. Acad. Sci. USA 92,7085-7089[Abstract/Free Full Text]
    48. 48
  48. Zhao, C., Ganz, T., Lehrer, R. I. (1995) The structure of porcine protegrin genes FEBS Lett. 368,197-202[CrossRef][Medline]
    49. 49
  49. Zhao, C., Ganz, T., Lehrer, R. I. (1995) Structures of genes for two cathelin-associated antimicrobial peptides: prophenin-2 and PR-39 FEBS Lett. 376,130-134[CrossRef][Medline]
    50. 50
  50. Levy, O., Weiss, J., Zarember, K., Ooi, C. E., Elsbach, P. (1993) Antibacterial 15-kDa protein isoforms (p15s) are members of a novel family of leukocyte proteins J. Biol. Chem. 268,6058-6063[Abstract/Free Full Text]
    51. 51
  51. Moscinski, L., C., Hill, B. (1995) Molecular cloning of a novel myeloid granule protein J. Cell Biochem. 59,431-442[CrossRef][Medline]
    52. 52
  52. Basanez, G., Shinnar, A. E., Zimmerberg, J. (2002) Interaction of hagfish cathelicidin antimicrobial peptides with model lipid membranes FEBS Lett. 532,115-120[CrossRef][Medline]
    53. 53
  53. Zanetti, M., Litteri, L., Gennaro, R., Horstmann, H., Romeo, D. (1990) Bactenecins, defense polypeptides of bovine neutrophils, are generated from precursor molecules stored in the large granules J. Cell Biol. 111,1363-1371[Abstract/Free Full Text]
    54. 54
  54. Gennaro, R., Dewald, B., Horisberger, U., Gubler, H. U., Baggiolini, M. A. (1983) Novel type of cytoplasmic granule in bovine neutrophils J. Cell Biol. 96,1651-1661[Abstract/Free Full Text]
    55. 55
  55. Scocchi, M., Skerlavaj, B., Romeo, D., Gennaro, R. (1992) Proteolytic cleavage by neutrophil elastase converts inactive storage proforms to antibacterial bactenecins Eur. J. Biochem. 209,589-595[Medline]
    56. 56
  56. Zanetti, M., Litteri, L., Griffiths, G., Gennaro, R., Romeo, D. (1991) Stimulus-induced maturation of probactenecins, precursors of neutrophil antimicrobial polypeptides J. Immunol. 146,4295-4300[Abstract]
    57. 57
  57. Cole, A. M., Shi, J., Ceccarelli, A., Kim, Y. H., Park, A., Ganz, T. (2001) Inhibition of neutrophil elastase prevents cathelicidin activation and impairs clearance of bacteria from wounds Blood 97,297-304[Abstract/Free Full Text]
    58. 58
  58. Sorensen, O., Arnljots, K., Cowland, J. B., Bainton, D. F., Borregaard, N. (1997) The human antibacterial cathelicidin, hCAP-18, is synthesized in myelocytes and metamyelocytes and localized to specific granules in neutrophils Blood 90,2796-2803[Abstract/Free Full Text]
    59. 59
  59. Sorensen, O. E., Follin, P., Johnsen, A. H., Calafat, J., Tjabringa, G. S., Hiemstra, P. S., Borregaard, N. (2001) Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3 Blood 97,3951-3959[Abstract/Free Full Text]
    60. 60
  60. Sorensen, O. E., Gram, L., Johnsen, A. H., Andersson, E., Bangsboll, S., Tjabringa, S. G., Hiemstra, P. S., Malm, J., Egesten, A., Borregaard, N. (2003) Processing of seminal plasma hCAP-18 to ALL-38 by gastricsin, a novel mechanism of generating antimicrobial peptides in vagina J. Biol. Chem. (epub ahead of print).
    61. 61
  61. Travis, S. M., Anderson, N. N., Forsyth, W. R., Espiritu, C., Conway, B. D., Greenberg, E. P., McCray, P. B., Jr, Lehrer, R. I., Welsh, M. J., Tack, B. F. (2000) Bactericidal activity of mammalian cathelicidin-derived peptides Infect. Immun. 68,2748-2755[Abstract/Free Full Text]
    62. 62
  62. Zanetti, M., Gennaro, R., Skerlavaj, B., Tomasinsig, L., Circo, R. (2002) Cathelicidin peptides as candidates for a novel class of antimicrobials Curr. Pharm. Des. 8,779-793[CrossRef][Medline]
    63. 63
  63. Zaiou, M., Nizet, V., Gallo, R. L. (2003) Antimicrobial and protease inhibitory functions of the human cathelicidin (hCAP18/LL-37) prosequence J. Invest. Dermatol. 120,810-816[CrossRef][Medline]
    64. 64
  64. Storici, P., Tossi, A., Lenarcic, B., Romeo, D. (1996) Purification and structural characterization of bovine cathelicidin, precursors of antimicrobial peptides Eur. J. Biochem. 238,769-776[Medline]
    65. 65
  65. Zanetti, M., Gennaro, R., Scocchi, M., Skerlavaj, B. (2000) Structure and biology of cathelicidins Adv. Exp. Med. Biol. 479,203-218[Medline]
    66. 66
  66. Sanchez, J. F., Hoh, F., Strub, M. P., Aumelas, A., Dumas, C. (2002) Structure of the cathelicidin motif of protegrin-3 precursor: structural insights into the activation mechanism of an antimicrobial protein Structure (Camb) 10,1363-1370
    67. 67
  67. Verbanac, D., Zanetti, M., Romeo, D. (1993) Chemotactic and protease-inhibiting activities of antibiotic peptide precursors FEBS Lett. 317,255-258[CrossRef][Medline]
    68. 68
  68. Frohm, M., Gunne, H., Bergman, A. C., Agerberth, B., Bergman, T., Boman, A., Liden, S., Jornvall, H., Boman, H. G. (1996) Biochemical and antibacterial analysis of human wound and blister fluid Eur. J. Biochem. 237,86-92[Medline]
    69. 69
  69. Ong, P. Y., Ohtake, T., Brandt, C., Strickland, I., Boguniewicz, M., Ganz, T., Gallo, R. L., Leung, D. Y. (2002) Endogenous antimicrobial peptides and skin infections in atopic dermatitis N. Engl. J. Med. 347,1151-1160[Abstract/Free Full Text]
    70. 70
  70. Andersson, E., Sorensen, O. E., Frohm, B., Borregaard, N., Egesten, A., Malm, J. (2002) Isolation of human cationic antimicrobial protein-18 from seminal plasma and its association with prostasomes Hum. Reprod. 17,2529-2534[Abstract/Free Full Text]
    71. 71
  71. Wang, Y., Agerberth, B., Lothgren, A., Almstedt, A., Johansson, J. (1998) Apolipoprotein A-I binds and inhibits the human antibacterial/cytotoxic peptide LL-37 J. Biol. Chem. 273,33115-33118[Abstract/Free Full Text]
    72. 72
  72. Sorensen, O., Bratt, T., Johnsen, A. H., Madsen, M. T., Borregaard, N. (1999) The human antibacterial cathelicidin, hCAP-18, is bound to lipoproteins in plasma J. Biol. Chem. 274,22445-22451[Abstract/Free Full Text]
    73. 73
  73. Schmidtchen, A., Frick, I. M., Andersson, E., Tapper, H., Bjorck, L. (2002) Proteinases of common pathogenic bacteria degrade and inactivate the antibacterial peptide LL-37 Mol. Microbiol. 46,157-168[CrossRef][Medline]
    74. 74
  74. Agerberth, B., Charo, J., Werr, J., Olsson, B., Idali, F., Lindbom, L., Kiessling, R., Jornvall, H., Wigzell, H., Gudmundsson, G. H. (2000) The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations Blood 96,3086-3093[Abstract/Free Full Text]
    75. 75
  75. Di Nardo, A., Vitiello, A., Gallo, R. L. (2003) Cutting edge: mast cell antimicrobial activity is mediated by expression of cathelicidin antimicrobial peptide J. Immunol. 170,2274-2278[Abstract/Free Full Text]
    76. 76
  76. Frohm Nilsson, M., Sandstedt, B., Sorensen, O., Weber, G., Borregaard, N., Stahle-Backdahl, M. (1999) The human cationic antimicrobial protein (hCAP-18), a peptide antibiotic, is widely expressed in human squamous epithelia and colocalizes with interleukin-6 Infect. Immun. 67,2561-2566[Abstract/Free Full Text]
    77. 77
  77. Bals, R., Wang, X., Zasloff, M., Wilson, J. M. (1998) The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface Proc. Natl. Acad. Sci. USA 95,9541-9546[Abstract/Free Full Text]
    78. 78
  78. Murakami, M., Ohtake, T., Dorschner, R. A., Schittek, B., Garbe, C., Gallo, R. L. (2002) Cathelicidin anti-microbial peptide expression in sweat, an innate defense system for the skin J. Invest. Dermatol. 119,1090-1095[CrossRef][Medline]
    79. 79
  79. Murakami, M., Ohtake, T., Dorschner, R. A., Gallo, R. L. (2002) Cathelicidin antimicrobial peptides are expressed in salivary glands and saliva J. Dent. Res. 81,845-850[Abstract/Free Full Text]
    80. 80
  80. Malm, J., Sorensen, O., Persson, T., Frohm-Nilsson, M., Johansson, B., Bjartell, A., Lilja, H., Stahle-Backdahl, M., Borregaard, N., Egesten, A. (2000) The human cationic antimicrobial protein (hCAP-18) is expressed in the epithelium of human epididymis, is present in seminal plasma at high concentrations, and is attached to spermatozoa Infect. Immun. 68,4297-4302[Abstract/Free Full Text]
    81. 81
  81. Hammami-Hamza, S., Doussau, M., Bernard, J., Rogier, E., Duquenne, C., Richard, Y., Lefevre, A., Finaz, C. (2001) Cloning and sequencing of SOB3, a human gene coding for a sperm protein homologous to an antimicrobial protein and potentially involved in zona pellucida binding Mol. Hum. Reprod. 7,625-632[Abstract/Free Full Text]
    82. 82
  82. Dorschner, R. A., Pestonjamasp, V. K., Tamakuwala, S., Ohtake, T., Rudisill, J., Nizet, V., Agerberth, B., Gudmundsson, G. H., Gallo, R. L. (2001) Cutaneous injury induces the release of cathelicidin anti-microbial peptides active against group A Streptococcus J. Invest. Dermatol. 117,91-97[CrossRef][Medline]
    83. 83
  83. Frohm, M., Agerberth, B., Ahangari, G., Stahle-Backdahl, M., Liden, S., Wigzell, H., Gudmundsson, G. H. (1997) The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders J. Biol. Chem. 272,15258-15263[Abstract/Free Full Text]
    84. 84
  84. Putsep, K., Carlsson, G., Boman, H. G., Andersson, M. (2002) Deficiency of antibacterial peptides in patients with morbus Kostmann: an observation study Lancet 360,1144-1149[CrossRef][Medline]
    85. 85
  85. Islam, D., Bandholtz, L., Nilsson, J., Wigzell, H., Christensson, B., Agerberth, B., Gudmundsson, G. (2001) Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator Nat. Med. 7,180-185[CrossRef][Medline]
    86. 86
  86. Nizet, V., Ohtake, T., Lauth, X., Trowbridge, J., Rudisill, J., Dorschner, R. A., Pestonjamasp, V., Piraino, J., Huttner, K., Gallo, R. L. (2001) Innate antimicrobial peptide protects the skin from invasive bacterial infection Nature 414,454-457[CrossRef][Medline]
    87. 87
  87. Bals, R., Weiner, D. J., Meegalla, R. L., Wilson, J. M. (1999) Transfer of a cathelicidin peptide antibiotic gene restores bacterial killing in a cystic fibrosis xenograft model J. Clin. Invest. 103,1113-1117[Medline]
    88. 88
  88. Bals, R., Weiner, D. J., Moscioni, A. D., Meegalla, R. L., Wilson, J. M. (1999) Augmentation of innate host defense by expression of a cathelicidin antimicrobial peptide Infect. Immun. 67,6084-6089[Abstract/Free Full Text]
    89. 89
  89. Larrick, J. W., Hirata, M., Balint, R. F., Lee, J., Zhong, J., Wright, S. C. (1995) Human CAP18: a novel antimicrobial lipopolysaccharide-binding protein Infect. Immun. 63,1291-1297
    90. 90
  90. Kirikae, T., Hirata, M., Yamasu, H., Kirikae, F., Tamura, H., Kayama, F., Nakatsuka, K., Yokochi, T., Nakano, M. (1998) Protective effects of a human 18-kilodalton cationic antimicrobial protein (CAP18)-derived peptide against murine endotoxemia Infect. Immun. 66,1861-1868[Abstract/Free Full Text]
    91. 91
  91. Turner, J., Cho, Y., Dinh, N. N., Waring, A. J., Lehrer, R. I. (1998) Activities of LL-37, a cathelin-associated antimicrobial peptide of human neutrophils Antimicrob. Agents Chemother. 42,2206-2214[Abstract/Free Full Text]
    92. 92
  92. Scott, M. G., Davidson, D. J., Gold, M. R., Bowdish, D., Hancock, R. E. (2002) The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses J. Immunol. 169,3883-3891[Abstract/Free Full Text]
    93. 93
  93. Hirata, M., Shimomura, Y., Yoshida, M., Morgan, J. G., Palings, I., Wilson, D., Yen, M. H., Wright, S. C., Larrick, J. W. (1994) Characterization of a rabbit cationic protein (CAP18) with lipopolysaccharide-inhibitory activity Infect. Immun. 62,1421-1426[Abstract/Free Full Text]
    94. 94
  94. Tack, B. F., Sawai, M. V., Kearney, W. R., Robertson, A. D., Sherman, M. A., Wang, W., Hong, T., Boo, L. M., Wu, H., Waring, A. J., et al (2002) SMAP-29 has two LPS-binding sites and a central hinge Eur. J. Biochem. 269,1181-1189[Medline]
    95. 95
  95. Larrick, J. W., Hirata, M., Zheng, H., Zhong, J., Bolin, D., Cavaillon, J. M., Warren, H. S., Wright, S. C. (1994) A novel granulocyte-derived peptide with lipopolysaccharide-neutralizing activity J. Immunol. 152,231-240[Abstract]
    96. 96
  96. De Yang,, Chen, Q., Schmidt, A. P., Anderson, G. M., Wang, J. M., Wooters, J., Oppenheim, J. J., Chertov, O. (2000) LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells J. Exp. Med. 192,1069-1074[Abstract/Free Full Text]
    97. 97
  97. Johansson, J., Gudmundsson, G. H., Rottenberg, M. E., Berndt, K. D., Agerberth, B. (1998) Conformation-dependent antibacterial activity of the naturally occurring human peptide LL-37 J. Biol. Chem. 273,3718-3724[Abstract/Free Full Text]
    98. 98
  98. Le, Y., Murphy, P. M., Wang, J. M. (2002) Formyl-peptide receptors revisited Trends Immunol. 23,541-548[CrossRef][Medline]
    99. 99
  99. Niyonsaba, F., Iwabuchi, K., Someya, A., Hirata, M., Matsuda, H., Ogawa, H., Nagaoka, I. (2002) A cathelicidin family of human antibacterial peptide LL-37 induces mast cell chemotaxis Immunology 106,20-26[CrossRef][Medline]
    100. 100
  100. Niyonsaba, F., Someya, A., Hirata, M., Ogawa, H., Nagaoka, I. (2001) Evaluation of the effects of peptide antibiotics human beta-defensins-1/-2 and LL-37 on histamine release and prostaglandin D(2) production from mast cells Eur. J. Immunol. 31,1066-1075[CrossRef][Medline]
    101. 101
  101. Feger, F., Varadaradjalou, S., Gao, Z., Abraham, S. N., Arock, M. (2002) The role of mast cells in host defense and their subversion by bacterial pathogens Trends Immunol. 23,151-158[CrossRef][Medline]
    102. 102
  102. Sorensen, O., Cowland, J. B., Askaa, J., Borregaard, N. (1997) An ELISA for hCAP-18, the cathelicidin present in human neutrophils and plasma J. Immunol. Methods 206,53-59[CrossRef][Medline]
    103. 103
  103. Koczulla, R., Von Degenfeld, G., Kupatt, C., Krotz, F., Zahler, S., Gloe, T., Issbrucker, K., Unterberger, P., Zaiou, M., Lebherz, C., et al (2003) An angiogenic role for the human peptide antibiotic LL-37/hCAP-18 J. Clin. Invest. 111,1665-1672[CrossRef][Medline]
    104. 104
  104. Heilborn, J. D., Nilsson, M. F., Kratz, G., Weber, G., Sorensen, O., Borregaard, N., Stahle-Backdahl, M. (2003) The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium J. Invest. Dermatol. 120,379-389[CrossRef][Medline]
    105. 105
  105. Risso, A., Zanetti, M., Gennaro, R. (1998) Cytotoxicity and apoptosis mediated by two peptides of the innate immunity Cell. Immunol. 189,107-115[CrossRef][Medline]
    106. 106
  106. Risso, A., Braidot, E., Sordano, M. C., Vinello, A., Macrì, F., Skerlavaj, B., Zanetti, M., Gennaro, R., Bernardi, P. (2002) BMAP-28, an antibiotic peptide of innate immunity, induces cell death through opening of the mitochondrial permeability transition pore Mol. Cell. Biol. 22,1926-1935[Abstract/Free Full Text]
    107. 107
  107. Tomasinsig, L., Scocchi, M., Di Loreto, C., Artico, D., Zanetti, M. (2002) Inducible expression of an antimicrobial peptide of the innate immunity in polymorphonuclear leukocytes J. Leukoc. Biol. 72,1003-1010[Abstract/Free Full Text]
    108. 108
  108. Agerberth, B., Lee, J. Y., Bergman, T., Carlquist, M., Boman, H. G., Mutt, V., Jornvall, H. (1991) Amino acid sequence of PR-39. Isolation from pig intestine of a new member of the family of proline-arginine-rich antibacterial peptides Eur. J. Biochem. 202,849-854[Medline]
    109. 109
  109. Gallo, R. L., Ono, M., Povsic, T., Page, C., Eriksson, E., Klagsbrun, M., Bernfield, M. (1994) Syndecans, cell surface heparan sulfate proteoglycans, are induced by a proline-rich antimicrobial peptide from wounds Proc. Natl. Acad. Sci. USA 91,11035-11039[Abstract/Free Full Text]
    110. 110
  110. Bernfield, M., Kokenyesi, R., Kato, M., Hinkes, M. T., Spring, J., Gallo, R. L., Lose, E. J. (1992) Biology of the syndecans: a family of transmembrane heparan sulfate proteoglycans Annu. Rev. Cell Biol. 8,365-393[CrossRef][Medline]
    111. 111
  111. Chan, Y. R., Gallo, R. L. (1998) PR-39, a syndecan-inducing antimicrobial peptide, binds and affects p130(Cas) J. Biol. Chem. 273,28978-28985[Abstract/Free Full Text]
    112. 112
  112. Ohba, T., Ishino, M., Aoto, H., Sasaki, T. (1998) Interaction of two proline-rich sequences of cell adhesion kinase beta with SH3 domains of p130Cas-related proteins and a GTPase-activating protein, Graf Biochem. J. 330,1249-1254
    113. 113
  113. Tanaka, K., Fujimoto, Y., Suzuki, M., Suzuki, Y., Ohtake, T., Saito, H., Kohgo, Y. (2001) PI3-kinase p85{alpha} is a target molecule of proline-rich antimicrobial peptide to suppress proliferation of ras-transformed cells Jpn. J. Cancer Res. 92,959-967[CrossRef][Medline]
    114. 114
  114. Huang, H. J., Ross, C. R., Blecha, F. (1997) Chemoattractant properties of PR-39, a neutrophil antibacterial peptide J. Leukoc. Biol. 61,624-629[Abstract]
    115. 115
  115. Shi, J., Ross, C. R., Leto, T. L., Blecha, F. (1996) PR-39, a proline-rich antibacterial peptide that inhibits phagocyte NADPH oxidase activity by binding to Src homology 3 domains of p47 phox Proc. Natl. Acad. Sci. USA 93,6014-6018[Abstract/Free Full Text]
    116. 116
  116. Granger, D. N., Korthuis, R. J. (1995) Physiologic mechanisms of postischemic tissue injury Annu. Rev. Physiol. 57,311-332[Medline]
    117. 117
  117. Li, J., Post, M., Volk, R., Gao, Y., Li, M., Metais, C., Sato, K., Tsai, J., Aird, W., Rosenberg, R., et al (2000) PR-39, a peptide regulator of angiogenesis Nat. Med. 6,49-55[CrossRef][Medline]
    118. 118
  118. Habeck, M. (2000) Wielding more power over angiogenesis Mol. Med. Today 6,138-139[CrossRef][Medline]
    119. 119
  119. Gao, Y., Lecker, S., Post, M. J., Hietaranta, A. J., Li, J., Volk, R., Li, M., Sato, K., Saluja, A. K., Steer, M. L., et al (2000) Inhibition of ubiquitin-proteasome pathway-mediated I kappa B alpha degradation by a naturally occurring antibacterial peptide J. Clin. Invest. 106,439-448[Medline]
    120. 120
  120. Korthuis, R. J., Gute, D. C., Blecha, F., Ross, C. R. (1999) PR-39, a proline/arginine-rich antimicrobial peptide, prevents postischemic microvascular dysfunction Am. J. Physiol. 277,H1007-H1013
    121. 121
  121. Huchon, D., Madsen, O., Sibbald, M. J., Ament, K., Stanhope, M. J., Catzeflis, F., de Jong, W. W., Douzery, E. J. (2002) Rodent phylogeny and a timescale for the evolution of Glires: evidence from an extensive taxon sampling using three nuclear genes Mol. Biol. Evol. 19,1053-1065[Abstract/Free Full Text]
    122. 122
  122. Shariflou, M. R., Moran, C. (2000) Conservation within artiodactyls of an AATA interrupt in the IGF-I microsatellite for 19–35 million years Mol. Biol. Evol. 17,665-669[Abstract/Free Full Text]
    123. 123
  123. Goodman, M., Porter, C. A., Czelusniak, J., Page, S. L., Schneider, H., Shoshani, J., Gunnell, G., Groves, C. P. (1998) Toward a phylogenetic classification of Primates based on DNA evidence complemented by fossil evidence Mol. Phylogenet. Evol. 9,585-598[CrossRef][Medline]



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[Full Text] [PDF]

Home page
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Clin. Microbiol. Rev., April 1, 2006; 19(2): 315 - 337.
[Abstract] [Full Text] [PDF]

Home page
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Infect. Immun., April 1, 2006; 74(4): 2338 - 2352.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
N. Mookherjee, K. L. Brown, D. M. E. Bowdish, S. Doria, R. Falsafi, K. Hokamp, F. M. Roche, R. Mu, G. H. Doho, J. Pistolic, et al.
Modulation of the TLR-Mediated Inflammatory Response by the Endogenous Human Host Defense Peptide LL-37
J. Immunol., February 15, 2006; 176(4): 2455 - 2464.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. Xiao, Y. Cai, Y. R. Bommineni, S. C. Fernando, O. Prakash, S. E. Gilliland, and G. Zhang
Identification and Functional Characterization of Three Chicken Cathelicidins with Potent Antimicrobial Activity
J. Biol. Chem., February 3, 2006; 281(5): 2858 - 2867.
[Abstract] [Full Text] [PDF]

Home page
 J Antimicrob ChemotherHome page
W. Baranska-Rybak, A. Sonesson, R. Nowicki, and A. Schmidtchen
Glycosaminoglycans inhibit the antibacterial activity of LL-37 in biological fluids
J. Antimicrob. Chemother., February 1, 2006; 57(2): 260 - 265.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L. Tomasinsig, B. Skerlavaj, N. Papo, B. Giabbai, Y. Shai, and M. Zanetti
Mechanistic and Functional Studies of the Interaction of a Proline-rich Antimicrobial Peptide with Mammalian Cells
J. Biol. Chem., January 6, 2006; 281(1): 383 - 391.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. A. Nordahl, V. Rydengard, M. Morgelin, and A. Schmidtchen
Domain 5 of High Molecular Weight Kininogen Is Antibacterial
J. Biol. Chem., October 14, 2005; 280(41): 34832 - 34839.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
M. H. Braff, M. Zaiou, J. Fierer, V. Nizet, and R. L. Gallo
Keratinocyte Production of Cathelicidin Provides Direct Activity against Bacterial Skin Pathogens
Infect. Immun., October 1, 2005; 73(10): 6771 - 6781.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. GenomicsHome page
A. A. Patil, Y. Cai, Y. Sang, F. Blecha, and G. Zhang
Cross-species analysis of the mammalian {beta}-defensin gene family: presence of syntenic gene clusters and preferential expression in the male reproductive tract
Physiol Genomics, September 21, 2005; 23(1): 5 - 17.
[Abstract] [Full Text] [PDF]

Home page
 Innate ImmunityHome page
D. M.E. Bowdish and R. E.W. Hancock
Anti-endotoxin properties of cationic host defence peptides and proteins
Innate Immunity, August 1, 2005; 11(4): 230 - 236.
[Abstract] [PDF]

Home page
 Antimicrob. Agents Chemother.Home page
D. M. E. Bowdish, D. J. Davidson, M. G. Scott, and R. E. W. Hancock
Immunomodulatory Activities of Small Host Defense Peptides
Antimicrob. Agents Chemother., May 1, 2005; 49(5): 1727 - 1732.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. Deng, S. Chen, Q. Li, S.-c. Lyu, C. Clayberger, and A. M. Krensky
Granulysin, a Cytolytic Molecule, Is Also a Chemoattractant and Proinflammatory Activator
J. Immunol., May 1, 2005; 174(9): 5243 - 5248.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. Iimura, R. L. Gallo, K. Hase, Y. Miyamoto, L. Eckmann, and M. F. Kagnoff
Cathelicidin Mediates Innate Intestinal Defense against Colonization with Epithelial Adherent Bacterial Pathogens
J. Immunol., April 15, 2005; 174(8): 4901 - 4907.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
N. Borregaard, K. Theilgaard-Monch, J. B. Cowland, M. Stahle, and O. E. Sorensen
Neutrophils and keratinocytes in innate immunity--cooperative actions to provide antimicrobial defense at the right time and place
J. Leukoc. Biol., April 1, 2005; 77(4): 439 - 443.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
S. van Wetering, G. S. Tjabringa, and P. S. Hiemstra
Interactions between neutrophil-derived antimicrobial peptides and airway epithelial cells
J. Leukoc. Biol., April 1, 2005; 77(4): 444 - 450.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
J. Harder and J.-M. Schroder
Psoriatic scales: a promising source for the isolation of human skin-derived antimicrobial proteins
J. Leukoc. Biol., April 1, 2005; 77(4): 476 - 486.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. H. Braff, M. A. Hawkins, A. D. Nardo, B. Lopez-Garcia, M. D. Howell, C. Wong, K. Lin, J. E. Streib, R. Dorschner, D. Y. M. Leung, et al.
Structure-Function Relationships among Human Cathelicidin Peptides: Dissociation of Antimicrobial Properties from Host Immunostimulatory Activities
J. Immunol., April 1, 2005; 174(7): 4271 - 4278.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
P. Nyberg, M. Rasmussen, and L. Bjorck
{alpha}2-Macroglobulin-Proteinase Complexes Protect Streptococcus pyogenes from Killing by the Antimicrobial Peptide LL-37
J. Biol. Chem., December 17, 2004; 279(51): 52820 - 52823.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
O. Levy
Antimicrobial proteins and peptides: anti-infective molecules of mammalian leukocytes
J. Leukoc. Biol., November 1, 2004; 76(5): 909 - 925.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
A. Schaffner, C. C. King, D. Schaer, and D. G. Guiney
Induction and antimicrobial activity of platelet basic protein derivatives in human monocytes
J. Leukoc. Biol., November 1, 2004; 76(5): 1010 - 1018.
[Abstract] [Full Text] [PDF]

Home page
 Antimicrob. Agents Chemother.Home page
L. Tomasinsig, M. Scocchi, R. Mettulio, and M. Zanetti
Genome-Wide Transcriptional Profiling of the Escherichia coli Response to a Proline-Rich Antimicrobial Peptide
Antimicrob. Agents Chemother., September 1, 2004; 48(9): 3260 - 3267.
[Abstract] [Full Text] [PDF]

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