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Originally published online as doi:10.1189/jlb.0604367 on December 9, 2004

Published online before print December 9, 2004
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(Journal of Leukocyte Biology. 2005;77:444-450.)
© 2005 by Society for Leukocyte Biology

Interactions between neutrophil-derived antimicrobial peptides and airway epithelial cells

Sandra van Wetering, G. Sandra Tjabringa1 and Pieter S. Hiemstra2

Department of Pulmonology, Leiden University Medical Center, The Netherlands

2Correspondence: Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: P.S.Hiemstra{at}lumc.nl


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ABSTRACT
 
Most antimicrobial peptides have been discovered based on activity-guided purification procedures, which used assays to determine their antimicrobial activity. Nevertheless, recent studies have shown that antimicrobial peptides also exert a range of other functions. Based on these observations, antimicrobial peptides are now not only implicated in host defense against infection but also in other immune reactions, inflammation, and wound-repair processes. The activities of neutrophil defensins and the cathelicidin hCAP-18/LL-37, antimicrobial peptides that are abundantly expressed in the human neutrophil, are the subject of an increasing number of studies. Exposure to neutrophil defensins and hCAP-18/LL-37 results in increases in mediator expression and release, chemotaxis, and proliferation of inflammatory and epithelial cells and fibroblasts, and the mechanisms underlying these effects have been partly elucidated. This review is focused on the effects of neutrophil defensins and hCAP-18/LL-37 on airway epithelial cells.

Key Words: defensins • cathelicidins • neutrophils • inflammation


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INTRODUCTION
 
Neutrophil infiltration is a characteristic of a variety of inflammatory disorders. Upon arrival in the tissue, neutrophils may contribute to host defense against infection by ingestion and intracellular killing of microorganisms, but they may also cause tissue injury, modulate immunity, and contribute to repair processes. A variety of mediators are used by the neutrophil to exert these functions and include the production of reactive oxygen intermediates and lipid mediators and the release of granule constituents such as proteolytic enzymes. The azurophilic and specific granules of the neutrophil contain antimicrobial peptides that are transferred to the phagolysosome, where they contribute to intracellular killing of ingested microorganisms. However, these peptides can also be released into the extracellular space, where they not only contribute to extracellular killing of microorganisms but also affect the function of other cells in the tissue. The aim of this review is to discuss recent insight into the mechanisms by which the neutrophil antimicrobial peptides {alpha}-defensins and cathelicidins affect epithelial cell function. Effects of neutrophil defensins and cathelicidins on other cell types have been discussed extensively in other reviews (refs. [1 , 2 ], Bowdish et al., pages 451–459, this issue).


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NEUTROPHILS, TISSUE INJURY, AND WOUND REPAIR
 
The contribution of neutrophils to tissue injury is determined by a variety of factors, including influx of neutrophils into the tissue, local stimulation leading to release of mediators, as well as the balance between neutrophil apoptosis and necrosis. Neutrophil infiltration is mediated by the action of chemotactic factors such as chemokines and adhesive interactions with endothelial cells, tissue cells, and extracellular matrix. Such interactions are also involved in neutrophil stimulation, resulting in the release of mediators that modulate tissue injury and repair processes. Finally, phagocytosis of apoptotic neutrophils by tissue macrophages is an important route of removal of short-lived neutrophils from an inflamed tissue and serves to prevent release of toxic neutrophil components from senescent neutrophils [3 ], which may not only cause injury but are also involved in tissue-repair reactions. Neutrophils and other inflammatory cells have been shown to be recruited to the site of epithelial injury, where they contribute to repair by, e.g., releasing components that display growth-stimulatory activity as will be discussed in this review.

Our insight into the role of neutrophils in tissue injury is based on a wealth of studies involving animal models, cell cultures, and observational and intervention studies in humans. This has led to the conclusion that excessive stimulation of neutrophils contributes markedly to tissue injury. In our research, we have focused on interactions of neutrophils with airway epithelial cells in inflammatory lung disorders. Neutrophils have been implicated in a variety of such disorders, including acute respiratory distress syndrome, cystic fibrosis, exacerbations of asthma, chronic bronchitis, and chronic obstructive pulmonary disease (COPD) [4 ]. As cigarette smoking is by far the most important risk factor for the development of COPD [5 ], the contribution of cigarette smoke to neutrophil accumulation in the lung has received considerable attention. A large number of studies in animals and humans have demonstrated that cigarette smoking causes accumulation of neutrophils in lung tissue. Using radiolabeled neutrophils, MacNee and co-workers [6 ] showed that acute smoking in humans leads to retention of neutrophils in lung tissue, which may be the result of decreased deformability of neutrophils, increased expression of adhesion molecules, and generation of chemotactic signals. What are the mediators released by neutrophils that contribute to lung injury? Neutrophil-derived elastase is considered as an important mediator in causing the emphysematous changes in the lung parenchyma of patients with COPD, a conclusion that is supported by the observation more than 40 years ago that patients with a deficiency in the elastase inhibitor {alpha}1-proteinase inhibitor ({alpha}1-PI; also known as {alpha}1-antitrypsin) are at increased risk for the development of pulmonary emphysema [7 ]. Following the observation that {alpha}1-PI not only inhibits serine proteinases such as elastase but also blocks the cytotoxic activity of neutrophil defensins [8 ], recent studies went on to show that neutrophil defensins in peripheral lung tissue may also contribute to lung injury [9 , 10 ]. In addition to the azurophilic granule proteins, neutrophil defensins and elastase, neutrophils release a range of other mediators with direct or indirect cytotoxic potential. These mediators that are stored in the azurophilic or specific granules of the neutrophil include a wide range of proteinases, cationic, nonenzymatic peptides (e.g., hCAP-18/LL-37), chemokines, lipid mediators, and oxidants [4 ]. These molecules equip the neutrophil with the ability to cause injury to a vast range of cell types such as the airway epithelial cells. It is interesting that these molecules may also contribute to tissue remodeling by, e.g., increasing the number of mucus-producing cells in the airway epithelium, and to tissue-repair processes [11 ].


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ANTIMICROBIAL PEPTIDES OF THE NEUTROPHIL: NEUTROPHIL DEFENSINS AND hCAP-18/LL-37
 
As discussed above, neutrophil defensins and hCAP-18/LL-37 are antimicrobial peptides that are stored in the neutrophil granules. Antimicrobial peptides are effector molecules of innate immunity, which play a central role in host defense against infection. The capacity of the immune system to respond adequately to microbial exposure is largely dependent on the production of antimicrobial peptides. More than 800 eukaryotic antimicrobial peptides have been reported (http://www.bbcm.units.it/~tossi/pag2.htm), which have a broad spectrum of antimicrobial activity and are produced by various cell types. In mammals, these include inflammatory cells, such as neutrophils and macrophages, dendritic cells (DC), and T cells, but also resident cells, such as epithelial cells. Based on their structure, the antimicrobial peptides can be divided into several classes. Two major families of human antimicrobial peptides have been identified, the defensins and cathelicidins.

To date, various neutrophil-derived, antimicrobial peptides and proteins have been described, including lysozyme, lactoferrin, defensins, and the cathelicidin LL-37. In humans, the family of defensins is divided into two subfamilies: {alpha}- and ß-defensins [12 ], which are small (28–44 amino acids) cationic peptides and are distinguished from each other based on their tertiary structure. The {alpha}-defensins have a typical ß-sheet structure with three intramolecular cysteine bonds, which link cysteines 1-6, 2-4, and 3-5, whereas the cysteines in the ß-defensins are linked 1-5, 2-4, and 3-6. To date, six {alpha}-defensin peptides have been identified of which four members are present in neutrophils [human neutrophil peptides (HNP) 1–4]. These peptides, of which HNP-4 is least abundant, form 30–50% of the total protein content of the azurophilic granule of the neutrophil. In addition, they are reported to be present in a specific subset of lymphocytes and in kidney epithelial cells [13 , 14 ]. The other two members, human defensins (HD)-5 and -6, are found primarily in intestinal Paneth cells and in epithelial cells of the female genital tract (reviewed in refs. [15 , 16 ]). Expression of HD-5 mRNA was also reported in bronchial and nasal epithelial cells [17 ]. The family of the ß-defensins consists of four well-characterized members, human ß-defensins 1–4, and a larger number of ß-defensins (up to 28), which have been identified by computerized searching of the genome [18 19 20 ]. They are produced by keratinocytes and various other epithelial cells, including airway epithelial cells, and by monocytes/macrophages and DC [21 ]. However, the amount of most antimicrobial peptides produced by monocytes, macrophages, and DC is much lower as compared with the amounts produced by neutrophils and epithelial cells, and their functional significance is unknown. Recently, a third subfamily of cyclic defensins has been identified in rhesus macaque monkeys, the {theta}-defensins, where their gene identified in humans does not result in production of a peptide, probably as a result of the presence of a stop codon [22 ].

Cathelicidins are composed of an N-terminal cathelin domain, which is highly conserved among a range of species and a more structurally diverse C-terminal domain [23 ]. This latter domain is released from the cathelin domain by proteolytic cleavage. LL-37 is the C-terminal domain of hCAP-18 and is the only human member of the cathelicidin family of antimicrobial peptides. It is a 37-mer peptide that forms a cationic, amphipatic {alpha}-helix and contains two N-terminal leucines. This structure allows it to insert into eukaryotic and prokaryotic membranes, resulting in cell death, possibly by a detergent-like effect on membrane integrity [24 ]. hCAP-18/LL-37 was first identified in neutrophils (which contain 0.627 µg per million cells; ref. [25 ]) and subsequently, shown to be produced by other cell types, including epithelial cells, natural killer cells, {gamma}{delta} T cells, monocytes, and mast cells (reviewed by Zanetti [23 ]). Two proteinases have been identified as being principally involved in the release of the cationic {alpha}-helical peptide LL-37 from the C-terminus of hCAP-18. Proteinase 3 is involved in the cleavage of hCAP-18 released from neutrophils [26 ], whereas the prostate enzyme gastricsin mediates cleavage of hCAP-18 produced by the epididymis [27 ].


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EFFECTS OF NEUTROPHIL DEFENSINS AND LL-37 ON EPITHELIAL CELL FUNCTION
 
Defensins and LL-37 are key components of the human innate host defense system and play an important role in neutrophil-mediated microbial killing. Indirect evidence for their role in neutrophil antimicrobial activity comes from patients with a nonselective deficiency in these peptides [28 , 29 ]. When released into the extracellular environment, these peptides can exert other activities that increase host defense but may also be potentially harmful. Soon after their initial characterization as human neutrophil antimicrobials [30 ], the cytotoxic and chemotactic activities of neutrophil defensins were discovered [31 , 32 ]. Subsequently, various other activities were discovered, which indicate a broad role for neutrophil defensins in innate and adaptive immunity and in wound repair (reviewed in refs. [1 , 2 ]).

Potential role of defensins and LL-37 in lung inflammation
We have extensively studied the modulation of airway epithelial cell function by neutrophil defensins, and from these in vitro studies, it appears that the nature of the effect of defensins is concentration-dependent (Fig. 1 ). At concentrations >50 µg/ml, defensins display cytotoxic activity toward various cell types including airway epithelial cells [8 , 33 ]. In addition, at these concentrations, defensins induce the release of the neutrophil chemoattractants interleukin (IL)-8 and epithelial neutrophil-activating protein 78 by airway epithelial cells [34 , 35 ]. These results suggest that defensins may indirectly promote additional recruitment and possibly activation of neutrophils at the site of inflammation. Increased plasma defensin levels have been described in various inflammatory diseases, and elevated levels (concentrations up to 1.5 mg/ml can be reached) of defensins are found in lung secretions of patients with a variety of inflammatory lung diseases [36 ]. The observation that intratracheal administration of defensins in mice causes acute lung inflammation and dysfunction [10 ] suggests that the cytotoxic effects of defensins play a role in vivo. However, the pathophysiological role of defensins at the site of inflammation is difficult to assess, as the activity of defensins is also under control of proteins such as {alpha}1-PI and {alpha}2-macroglobulin. These proteins have been shown to abrogate the cytotoxic effects as well as the ability of defensins to induce IL-8 in epithelial cells [8 ]. It is interesting that these compounds appear to inhibit defensin functions selectively, as illustrated by the observation that {alpha}1-PI does not affect defensin-induced epithelial cell proliferation [37 ]. Therefore, the presence of adequate concentrations of {alpha}1-PI and {alpha}2-macroglobulin may be critical in controlling the harmful extracellular effects of defensins. In line with these findings about the role of {alpha}1-PI, a recent paper demonstrated that neutrophil defensins may contribute to airways inflammation and tissue destruction in the lower respiratory tract of {alpha}1-PI-deficient patients [9 ].



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  		Figure 1. Concentration-dependent effect of neutrophil defensins on epithelial injury and repair. Following injury to a normal layer of airway epithelial cells consisting of basal cells, ciliated, and nonciliated cells, and mucin-producing goblet cells, a repair process is initiated, resulting in restoration of a mucociliary epithelium following injury. Neutrophil defensins affect the repair process at various stages, and the nature of their effect is determined by the local concentration.

Like neutrophil defensins, hCAP-18/LL-37 not only displays antimicrobial activity but also a range of other activities. Several studies have shown that hCAP-18/LL-37 is increased during inflammation [38 39 40 ]. At high concentrations, LL-37 displays cytotoxic activities toward eukaryotic cells. In addition, like neutrophil defensins, LL-37 also increases chemokine release from lung epithelial cells [41 , 42 ]. Furthermore, LL-37 is chemotactic for neutrophils, eosinophils, monocytes, T cells, and mast cells [43 44 45 ] and causes activation of inflammatory cells, as demonstrated by its ability to affect release of cytokines and other mediators by monocytes and macrophages [41 , 46 ] and mast cells [47 ] and to modulate DC function [48 ]. It is interesting that a recent study showed that the local milieu may regulate the ability of LL-37 to contribute to host defense against infection and inflammation. By studying LL-37 and related peptides secreted into human sweat, Murakimi et al. [49 ] showed that LL-37 is processed to smaller peptides, which do display antimicrobial activity but have lost their ability to induce IL-8 production by keratinocytes, suggesting modulation of antimicrobial and immunomodulatory activities.

Role of defensins and LL-37 in epithelial wound repair
An intact epithelial layer is essential for an effective host defense system. Therefore, following epithelial injury, a repair response is initiated. This repair process comprises subsequent events such as epithelial proliferation, migration, and differentiation, processes that are predominantly mediated by growth factors and their receptors. Among these receptors, the epidermal growth factor receptor (EGFR) and its downstream signaling pathways including the extracellular-regulated kinases 1 and 2 (ERK1/2) pathway are considered to be the most important. In addition, the epithelial repair response is often accompanied by the influx of inflammatory cells such as neutrophils. Upon activation, neutrophils release various proteins, including defensins, to protect the injured site from invading microbes, but they may also contribute to the epithelial repair response. This was suggested by a study in rats showing that depletion of neutrophils results in an impaired epithelial proliferation following ozone-induced injury [50 ]. In line with this observation, various groups, including our own, showed that neutrophil defensins enhance proliferation of human lung [37 ] and retinal epithelial cells [51 ], renal carcinoma cell [13 ], and murine fibroblasts [51 ]. Subsequent studies revealed that defensins affect various phases of the wound-repair process (Fig. 1) . Using the airway epithelial cell line NCI-H292 as a model, we showed that defensins at low concentrations (<10 µg/ml) accelerate epithelial wound closure [52 ]. This was a result of their ability to act as a direct chemoattractant for epithelial cells, causing epithelial cell migration as well as their ability to enhance epithelial cell proliferation. Signal-transduction studies revealed that the defensin-mediated wound closure required activation of the EGFR and ERK1/2 signaling (Fig. 2 ). Defensins caused two waves of phosphorylation of ERK1/2: an early (5 min–1 h) and a late (10 h) phase of activation. Only this late phase was blocked by anti-EGFR antibodies. This suggests that defensins cause initial EGFR-independent activation of ERK1/2, which results in shedding of membrane-anchored EGFR ligands that subsequently bind and activate EGFR. This proposed mechanism is supported by the reported observation that shedding of the EGFR ligands transforming growth factor {alpha} (TGF-{alpha}) and heparin-binding EGFR is regulated by ERK1/2 and other MAPKs [53 , 54 ]. We also obtained evidence that defensins affect the final stage in the airway epithelial cell-repair process, which is cell differentiation. In the airways, epithelial differentiation is characterized by the presence of a subset of cells, which express and release mucins such as the glycoproteins MUC5B and MUC5AC. We observed that defensins induce the expression of MUC5B and MUC5AC in cells of the airway epithelial cell line NCI-H292 and thus, may contribute to epithelial cell differentiation. Nevertheless, these results also indicate that defensins may contribute to mucus hypersecretion and subsequent airway obstruction, features that are often observed in neutrophil-dominated diseases such as chronic bronchitis.



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  		Figure 2. Cellular effects and signal-transduction pathways activated by neutrophil defensins (HNP-1 to -3) and LL-37. Neutrophil defensins and LL-37 cause activation of the mitogen-activated protein kinase (MAPK) ERK1/2 in airway epithelial cells. Activation of ERK1/2 by LL-37 is mediated by ligand-dependent transactivation of the EGFR via metalloproteinase (MP)-mediated cleavage of membrane-anchored EGFR ligands. In contrast, neutrophil defensins cause rapid activation of ERK1/2, which is not mediated via EGFR. In this model, activated ERK1/2 causes MP-mediated shedding of membrane-anchored EGFR ligands, which subsequently activate EGFR.

We recently observed that LL-37 causes activation of airway epithelial cells, resulting in IL-8 release via transactivation of the EGFR [42 ] (Fig. 2) . This activation could be prevented by the MP inhibitor GM6001 and by neutralizing anti-EGFR antibodies, indicating that LL-37 activates the EGFR via MP-mediated cleavage of membrane-anchored EGFR ligands. The importance of the EGFR in wound-repair processes suggests an involvement of LL-37 in wound repair. Indeed, LL-37 stimulates wound-repair processes in human skin [55 ]. Angiogenic activity of LL-37, a mechanism that is mediated via activation of the formyl peptide receptor-like 1 (FPRL1) [56 ], suggests that LL-37 may mediate neovascularization of the repairing wound area. In addition to LL-37, the porcine neutrophil-derived cathelicidin PR-39 has been implicated in wound repair [57 ]. This conclusion was based on the observation that PR-39 induces expression of syndecans, surface molecules that may increase the interaction of growth factors with their receptors.

Various studies have demonstrated that other neutrophil products, including lactoferrin [58 ] and H2O2 [59 ], are involved in epithelial cell proliferation. A recent study from Wiedow and co-workers [60 ] showed that elastase mediates proliferation of keratinocytes via TGF-{alpha}-mediated activation of the EGFR. Detailed analysis of lung tissue from patients with inflammatory lung disorders shows an association between neutrophil influx and epithelial cell proliferation. Bronchial biopsies obtained from chronic bronchitis patients, who have increased neutrophil numbers, showed an increased proportion of proliferating cells as compared with healthy and asthmatic subjects who have lower neutrophil numbers [61 ]. This may suggest that epithelial cell proliferation and neutrophil influx may be associated features in chronic bronchitis. However, whereas neutrophil-mediated cell proliferation may be beneficial for the host, uncontrolled stimulation of cell proliferation may have detrimental effects. Abnormal epithelial changes, such as squamous and mucus cell metaplasia, which occur frequently in chronic bronchitis, are also often associated with neutrophilic inflammation. Although it is not known whether defensins may contribute to mucus hypersecretion and squamous metaplasia, we recently demonstrated by immunohistochemistry that the presence of neutrophil defensins was accompanied by an increased number of proliferating cells in squamous metaplastic areas [62 ].


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NEUTROPHIL DEFENSINS, LL-37, AND THEIR POSSIBLE ROLE IN CANCER
 
A variety of recent studies have indicated a possible role of antimicrobial peptides such as neutrophil defensins and LL-37 in tumor progression. However, definitive proof of their involvement has not yet been obtained. As discussed in the previous section, neutrophil defensins are mitogenic and cytotoxic for a variety of cell types, including airway epithelial cells, depending on the local concentration (Fig. 1) . Based on these properties, neutrophil defensins can play a possible role in cancer by causing tumor cells to proliferate or by killing these cells. Indeed, such a role of neutrophil defensins in renal carcinoma was suggested by a recent study showing that renal cell carcinoma cells produce HNP-1 to -3 and affect proliferation of a subset of malignant cells in vitro [13 ]. Although neutrophil defensins also cause proliferation of lung tumor cell lines [37 ], their role in the establishment of lung cancer is not known. However, it is known that chronic airways inflammation (which can be associated with high levels of neutrophil defensins and hCAP-18/LL-37) predisposes to the development of lung cancer [63 ]. In contrast to their possible involvement in tumor progression as a result of their mitogenic activity, neutrophil defensins also display potential anti-tumor activity by inhibiting angiogenesis [64 ]. Based on this observation, it was suggested that a novel class of angiogenesis inhibitors could be developed using the structure of neutrophil defensins as a starting point.

In contrast to the inhibitory activity of neutrophil defensins, LL-37 displays angiogenic activity [56 ]. Other studies indicated that LL-37 may display selective cytotoxic activity against tumor cells. A 27-mer peptide of hCAP-18 (hCAP-18109–135) induces apoptosis in cells of the human oral squamous cell carcinoma cell line SAS-HI but not in fibroblasts and the keratinocyte cell line HaCaT [65 ]. The observation that hCAP-18109–135 induces caspase-independent apoptosis in oral squamous cell carcinoma but not in the normal cells that were evaluated suggests a differential sensitivity of tumor and normal cells. In addition to the possible link between defensins and tumor development, the effects of LL-37 on tumor cell apoptosis, EGFR activation, and wound repair and angiogenesis imply a role for LL-37 in tumor development. It is, however, evident that such a role of neutrophil defensins and LL-37 in tumor development is complex, as tumor-promoting and inhibitory actvities have been reported. Therefore, a detailed analysis is required to understand their role in vivo.


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PUTATIVE RECEPTORS INVOLVED IN THE EFFECTS OF DEFENSINS AND LL-37 ON CELL FUNCTION
 
The mechanism by which defensins exert their activities on airway epithelial cells is unknown. Most of the cationic antimicrobial peptides such as defensins interact with the bacterial membrane by disrupting the order of the phospholipid layer, causing loss of membrane integrity and subsequent lysis of the cells [66 ]. Such a mechanism may in part also explain the cytotoxic effects of defensins on eukaryotic cells. In addition, antimicrobial peptides may target the mitochondrial membrane directly and thus display cytotoxic activity [65 , 67 ]. It is not known whether defensins exert some of their effects on epithelial cells by acting as a ligand for cellular receptors. Whereas we did observe that neutrophil defensins increase EGFR phosphorylation in epithelial cells [52 ], a direct interaction between defensins and EGFR is unlikely. A possible candidate defensin receptor was identified in a study showing that the ability of defensins to inhibit phenylephrine-stimulated contraction of coronary smooth muscle cells is mediated via the low-density lipoprotein receptor-related protein/{alpha}2-macroglobulin receptor [68 ]. However, whether this receptor plays a role in mediating the effects of defensins on epithelial cells is not clear. In addition, as defensin-induced chemotaxis of T cells and DC was shown to be pertussis toxin-sensitive, the involvement of a G-protein-coupled receptor has been suggested. In line with these data is the recent observation that defensin-induced IL-8 release is blocked by an antagonist of purinergic P2 receptors and an antisense oligonucleotide directed against the G-protein-coupled purinergic receptor P2Y6 [69 ] (Fig. 3 ). This suggests that defensins may act via the P2Y receptor itself or indirectly via the activation of the extracellular purines adenosine 5'-triphosphate (ATP) or uridine 5-diphosphate (UDP), which are known to activate P2Y receptors [71 ]. The release of these nucleotides and subsequent activation of the purine receptor are often induced upon epithelial cell damage or by inflammatory stimuli. It is commonly believed that they play a role in ion transport across the epithelial surface. In addition, these nucleotides and their receptors are implicated in cellular processes such as epithelial proliferation [72 ] and are able to activate the EGFR [73 ]. It is interesting that all these events are also affected by neutrophil defensins.



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  		Figure 3. Putative role of P2 receptor nucleotide signaling in the activation of eukaryotic cells by neutrophil defensins (HNP-1 to -3) and LL-37. Recent studies show the involvement of ligand-gated P2X receptors in activation of monocytes by LL-37 [70 ] and that of G-protein-coupled P2Y receptors in activation of A549 lung epithelial cells by neutrophil defensins [69 ]. See text for details. LPS, Lipopolysaccharide.

Receptors involved in LL-37-mediated chemotaxis of neutrophils and T lymphocytes were studied using a cell line transfected with the FPRL1, indicating that this receptor was involved in LL-37-induced chemotaxis [43 ]. We recently extended these findings by showing that LL-37-mediated chemotaxis of neutrophils and eosinophils is inhibited by the formyl peptide-receptor antagonistic peptide tBoc-methionyl-1-leucyl-1-phenylalanine [45 ]. In addition, the angiogenic activity of LL-37 appears to be mediated via endothelial FPRL1 [56 ]. Elssner et al. [70 ] provided indirect evidence for a direct interaction of LL-37 with the P2X7 purinergic receptor on monocytes, which acts as a nucleotide-gated channel. Various studies have shown that the P2X7 receptor mediates ATP-induced release of IL-1ß from LPS-primed monocytes [74 ]. In the study by Elssner et al. [70 ], the possibility that LL-37 would act via the induction of release of ATP was excluded by showing that apyrase, which hydrolizes ATP, does not affect LL-37-induced IL-1ß release. We have demonstrated involvement of the EGFR in LL-37-induced activation of the MAPK ERK1/2 in airway epithelial cells and release of IL-8 from these cells. As activation was inhibited by anti-EGFR-ligand antibodies and by a MP inhibitor, transactivation of the EGFR was suggested. In contrast to studies showing involvement of G-protein-coupled receptor in transactivation of EGFR, pertussis toxin did not inhibit LL-37-induced activation. Whether LL-37 may penetrate the cell membrane and activate intracellular pathways resulting in ERK1/2 activation and IL-8 release or may bind to a yet-unidentified receptor is unknown.


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CONCLUDING REMARKS
 
Neutrophil defensins and hCAP-18/LL-37 are present in large amounts in the neutrophil, secreted upon activation, and their concentrations are increased in a wide variety of inflammatory disorders. Their marked ability to restrict microbial growth and affect innate and adaptive immunity and their involvement in wound-repair processes are of interest for our understanding of the biological role of these peptides in health and disease but also for the development of antimicrobial peptides for therapeutic applications. This application is of special interest in view of the growing resistance of various bacteria to conventional antibiotics. Understanding the complex networks involved in host defense at the mucosal surfaces and the role of antimicrobial peptides in controlling infection, inflammation, and repair may lead to the development of a new class of antibiotics with multiple activities.


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ACKNOWLEDGEMENTS
 
The studies in the authors’ laboratory are supported by grants from the Netherlands Asthma Foundation, The Netherlands Organization for Scientific Research (NWO), and AstraZeneca.


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FOOTNOTES
 
1 Current address: Academic Center for Dentistry Amsterdam (ACTA), Vrije Universiteit, Department of Oral Cell Biology, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. Back

Received June 28, 2004; revised October 24, 2004; accepted October 26, 2004.


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