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(Journal of Leukocyte Biology. 2000;68:779-784.)
© 2000 by Society for Leukocyte Biology

Expression of mammalian defensin genes

Vicki Kaiser and Gill Diamond

Department of Anatomy, Cell Biology and Injury Sciences, UMDNJ-New Jersey Medical School, Newark

Correspondence: Gill Diamond, Ph.D., Department of Anatomy, Cell Biology and Injury Sciences, UMDNJ-New Jersey Medical School, 185 South Orange Ave., Newark, NJ 07103. E-mail: gdiamond{at}umdnj.edu


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ABSTRACT
 
Antimicrobial peptides are a prevalent mechanism of host defense found throughout nature. In mammals, defensins are among the most abundant of these broad-spectrum antibiotics, and are expressed in epithelial and hematopoietic cells. The defensin peptides are especially abundant in neutrophils; however, gene expression is limited to the promyelocyte stage. In epithelial cells, defensin genes are found as both constitutively expressed and inducible. Induction has been observed in vitro by stimulation with bacterial lipopolysaccharide as well as inflammatory mediators. In vivo, up-regulation of several defensin genes occurs in both infectious and inflammatory states. Gene regulation occurs via signal transduction pathways common to other innate immune responses, utilizing transcription factors such as nuclear factor (NF)-{kappa}B and NF interleukin-6. Together, the data suggest a broad-based innate host defense whereby potent antimicrobial peptides are present to prevent initial colonization by pathogenic microorganisms. In addition, the recognition of bacteria coupled with a nascent inflammatory response can bolster this defense by a coordinated up-regulation of the peptides.

Key Words: antimicrobial peptides • host defense • innate immunity


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INTRODUCTION
 
Innate immunity provides an organism with a first line of host defense against pathogenic microorganisms. As opposed to adaptive immunity, this response is nonclonal, nonspecific, and ever present. In addition to its constitutive quality, there is a rapid response whereby components of innate immunity are produced after an initial challenge by pathogens. Among the cells that make up the arsenal of innate immunity are circulating phagocytic cells, such as neutrophils and macrophages, in addition to cells that line the mucosal epithelium. One common characteristic of cells from these two distinct lineages is the production of antimicrobial peptides, which act as part of the armamentarium of the cells to prevent microbial colonization. The peptides in phagocytic cells act as part of the oxygen-independent microbicidal pathway, whereas in epithelial cells, they are presumed to be secreted into the extracellular environment to provide antimicrobial activity. In both cases, the genes that encode these peptides can either be constitutively expressed or induced by inflammatory mediators and bacterial challenge. In this review, we will examine the gene expression of one family of mammalian antimicrobial peptides, the defensins. We will discuss their tissue-specific expression, inducibility, and the genetic elements that regulate their expression.

Antimicrobial peptides can be divided into numerous categories based on their primary and secondary structures but most of them maintain certain common structural characteristics. These include a cationic charge, due to arginine and lysine residues, and a greater ability to interact with bacterial membranes, due to an over-representation of hydrophobic amino acids. The peptides also exhibit a broad spectrum of antimicrobial activity, often including both gram-positive and gram-negative bacteria, fungi, and enveloped viruses. In addition, antimicrobial peptides are frequently found in families, where a single species may have numerous homologs expressed in the same cell type, suggesting complementary or synergistic activities between homologs. Lower organisms, such as amphibians and fish, express a variety of linear antimicrobial peptides in their skin secretions [1 , 2 ]. These exhibit an amphipathic {alpha}-helical structure and are similar to insect peptides, which are abundantly expressed in hemolymph [3; for reviews see ref. 4 ]. Mammals, on the other hand, express a variety of peptide families at a number of sites, and the most thoroughly studied family is that of the defensins.

Defensins are cationic peptides, 20–40 amino acids in length, containing six cysteines, which form three intramolecular disulfide bonds. They are classified as {alpha}-, ß-, or {theta}-defensins, based on the relative positions of these disulfide bonds. {alpha}-Defensins were first isolated from rabbit alveolar macrophages [5 ]. Subsequently, homologous peptides were discovered in the neutrophils of most species examined. These peptides are characterized by the maintenance of a six-cysteine consensus sequence as well as several other highly conserved amino acids [6 7 8 9 ]. They exhibit antimicrobial activity in vitro against bacteria [10 , 11 ], fungi [11 ], and enveloped viruses [12 ].

Homologous peptides were also found in the Paneth cells at the base of the crypts of Lieberkuhn in human [13 ], mouse [14 ], and rat [15 ] small intestine. These defensins, known as cryptdins, were the first indication that defensins could be expressed in both epithelial and myeloid cells. As opposed to the neutrophil defensins, which presumably function intracellularly, the small intestinal defensins are secreted into the lumen of the crypt [16 ].

As part of a study to define antimicrobial host defense of the mammalian airway, a basic, cysteine-rich peptide expressed in the bovine tracheal epithelium was discovered [17 ]. This molecule, tracheal antimicrobial peptide (TAP), exhibited numerous similarities to the {alpha}-defensins, but did not maintain the strict {alpha}-defensin cysteine-motif. Shortly thereafter, 13 new peptides were discovered in the bovine neutrophil, which also exhibited the same six-cysteine motif as TAP [18 ]. These discoveries resulted in the creation of a second class of defensins called the ß-defensins, and have now been identified alongside {alpha}-defensins in humans, mice, and rats [for review, see ref. 19 ]. A recently described third class of defensins, {theta}-defensins, exhibit a unique structure that is apparently the result of posttranslational processing [20 ]. These cyclic 18-residue peptides are the ligation product of two nine-residue peptides that are each encoded by a truncated cDNA.

As with all antimicrobial peptides studied to date, defensins are initially synthesized as larger precursors, which are processed to the mature, active peptide. The precursor to defensins is made as an 87- to 94-residue peptide consisting of a hydrophobic leader sequence, a short acidic propiece, followed by the mature sequence [21 ]. The proregion appears to act in charge neutralization of the highly cationic mature peptide, resulting in the inactivation of antimicrobial activity until processing is complete. However, this maturation process is specific for different defensin subtypes. Processing of the neutrophil defensins occurs during granulogenesis [21 ]. The active peptide is located in the granules of the mature neutrophil, and alternative processing can occur, resulting in isoforms differing in up to four additional amino acids on the amino terminus of the mature peptide [18 , 22 ]. In contrast, the defensins of the small intestines are secreted as prepropeptides, and the final activation processing step occurs in the lumen of the crypt. In the mouse, the lumenal processing enzyme has been identified as the matrix metalloproteinase matrilysin [23 ]. No active defensins were found in the intestinal crypts of matrilysin-deficient mice, and these mice were predisposed to intestinal infection of orally introduced bacteria.


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DEFENSIN GENE STRUCTURE
 
The genes encoding all classes of defensins are localized to a single chromosomal region in the human genome, 8p21-23. Their relative locations suggest their evolution from a single precursor, and that myeloid {alpha}-defensin genes evolved from Paneth cell {alpha}-defensin genes by duplication and divergence [24 , 25 ]. The number of defensin genes on chromosome 8 appears to vary within the population, suggesting that this provides a genetic component to individual resistance to infection [26 ].

The genes encoding the leukocyte {alpha}-defensins are comprised of three exons, with the first exon encoding a 5’ untranslated region. The remaining {alpha}- and ß-defensins have two exons, which are equivalent to exons two and three of the leukocyte {alpha}-defensins. The gene structure of the ß-defensins indicates a second subdivision. One subfamily, which includes human ß-defensin 2 (hBD2), has a relatively small (2 kb) intron and is characterized by inducible expression in epithelial cells (see below). The other subfamily, which includes human ß-defensin 1 (hBD1), has a large intron (about 10 kb), and is characterized by constitutive expression in a variety of cell types.


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DEFENSIN TISSUE EXPRESSION AND REGULATION
 
Both {alpha}- and ß-defensins are expressed in a variety of epithelial tissues, which serve as primary microbial interface sites. Tables 1 and 2 list several mammalian {alpha}- and ß-defensins identified to date: their tissue expression, inducibility, and regulatory elements. As can be seen from the tables, primary sources of defensins are myeloid, airway, and intestinal cells. Although multiple tissues may be listed for some defensins, the highest levels of gene expression are usually localized to one tissue type. For example, EBD has been identified in several bovine tissues, but mRNA levels are highest in the small intestines.


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  		Table 1. Mammalian {alpha}-Defensins

Both neutrophil and macrophage myeloid cells have served as rich sources of defensins. Numerous defensins have been isolated at high concentrations from membranous storage granules of neutrophils. The four {alpha}-defensins (HNP-1/-4), isolated from the azurophilic granules of human neutrophils [6 , 11 ], make up approximately 5–10% of the protein in these cells [27 ]. The dense granules of the bovine neutrophils have yielded 13 ß-defensins [18 ]. Although defensin proteins are present in the mature neutrophil, they are synthesized in the promyelocyte [21 ]. It is surprising to note that mouse neutrophils are devoid of defensins [28 ].

The airway is also a site of antimicrobial challenge as reflected in the numerous ß-defensins isolated from cow (TAP) [17 ], human (hBD1 / 2) [29 , 30 ], mouse (mBD-1, -2, -3) [31 32 33 34 ], and pig (pBD-1) [35 ]. In vitro data indicate an active role for these proteins in airway defense. For example, stimulation of cultured airway cells by lipopolysaccharide (LPS), interleukin-1ß (IL-1ß), or tumor necrosis factor {alpha} (TNF-{alpha}) results in increased mRNA levels of TAP [36 37 38 ], hBD2 [30 , 39 40 41 42 ], and mBD-2, -3 [32 , 34 ]. The bovine ß-defensin LAP is coordinately up-regulated with TAP but at much lower levels [38 ]. In contrast, hBD1 [41 , 43 ], mBD-1 [31 , 33 , 44 ], and pBD-1 [45 ] mRNA levels are unaffected by such inducers.

The correlative increase of defensin mRNA with bacterial stimulation is not limited to in vitro data. An increase of defensin mRNA in the presence of infection was detected by in situ hybridization in several in vivo studies. Increased defensin message was only detected in bovine intestinal tissue from cows testing positive for Mycobacterium paratuberculosis [46 ]. Likewise, increased defensin message was detected in lung tissue from mouse and a calf experimentally infected with Pseudomonas aeruginosa [32 ] or Pasteurella haemolytica [46 ], respectively. LAP expression was also increased in bovine tongue tissue in areas of inflammation but not in neighboring, normal tissue [47 ]. Finally, elevated hBD2 protein levels were only found in the plasma of patients with bacterial pneumonia [48 ]. These data provide increasing support for the role of defensins in preventing microbial pathogenesis.

Expression of the defensins within the gastrointestinal tract, specifically the small intestines, creates a unique situation. Here, the environment is much different than the sterile conditions of the lower lung and blood. Microbiota are an intrinsic part of the proper functioning of the lower gastrointestinal tract. Therefore, inherent in the role of the defensins is the prevention of bacterial colonization within and translocation from the lumen without disturbing the balance of the native flora. Enteric defensins have been characterized in humans (HD-5/-6) [13 , 49 ], mice (cryptdins) [14 ], rats (cryptdins) [15 ], and cows (EBD) [50 ]. In cows, the mRNA of EBD has been detected in high levels in the distal small intestines and colon; it is secreted as an active peptide, and its mRNA is induced by inflammatory mediators and microbial challenge. In contrast, humans, mice, and rats secrete {alpha}-defensins from crypt Paneth cells, which are then processed to an active peptide. Microbial challenge raises lumenal cryptdin protein levels by increasing Paneth cell secretions [51 ], and rat cryptdin mRNA levels are increased after hemorrhagic shock [15 ].


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DEFENSIN GENE REGULATION
 
The observation that relative levels of defensin proteins differ within the same and different tissues, and that some are inducible while others are constitutive, suggests that defensin gene regulation is important to the maintenance of a balanced spectrum of antimicrobial activity. Therefore, the identification of the regulatory elements and signaling pathways involved in defensin gene expression is of interest. Studies have shown consistencies in the gene expression of both TAP and the human homolog hBD2. For example, in vitro LPS induction of both genes is mediated by the LPS co-receptor CD14 and results in an increase of NF-{kappa}B activity [36 , 52 ]. In addition, the 5’ flanking region of both these genes contain consensus binding sites for the nuclear transcription factors NF-{kappa}B and nuclear factor interleukin 6 (NF IL-6) [37 , 53 ]. In vitro studies, in which bovine tracheal epithelial cells were transfected with reporter gene constructs, showed that both sites are necessary for TAP gene induction upon stimulation with LPS [37 ]. In the same study, gel mobility shift assays demonstrated that NF-{kappa}B binding was induced upon LPS treatment, whereas NF IL-6 binding was constitutive. However, the observation that TAP gene expression in bovine alveolar macrophage is not induced by LPS treatment suggests differences in tissue-specific regulation.

Differences from TAP are observed in the regulatory sites of two other bovine ß-defensin genes. The intestinal gene EBD lacks sequences for NF-{kappa}B, yet has been shown to be induced [50 ]. Like TAP, EBD retains the NF IL-6 consensus sequences but also contains a binding site for H-APF-1. It has been suggested that this factor cooperates with NF IL-6 in gene activation [50 ]. The constitutively expressed neutrophil defensin BNBD-4 also lacks an NF-{kappa}B site but retains NF IL-6 consensus sequences [54 ]. In BNBD-4, the recognition sequence for the myeloid-specific factor PEB2/CBF is also present, and this factor may be important for its myeloid expression [54 ].

Support of myeloid-specific regulation also comes from studies of the regulatory sequences of the HNP-1 and -3 genes. The observation that HNP-1 is more abundant in human neutrophils than HNP-3 suggests that regulation of the two genes may differ. However, reporter constructs transfected into human promyelocytic leukemia cells show that both genes were equally expressed. Although not important to the differential expression of the two genes, a CCAAT/enhancer-binding protein site was important for gene expression. In addition, promoter activities were very low in a nonhematopoietic cell line, suggesting that HNP expression is myeloid-specific [55 ]. Because HNP-2 is a proteolytic cleavage product of HNP-1 and/or HNP-3, the difference in the HNP-1/-3 protein levels was attributed to differential protein cleavage and indicates another means of defensin protein regulation.


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ADDITIONAL ROLES FOR DEFENSINS
 
The roles of defensins are not limited to antimicrobial activity. Independent of their isolation and characterization as antimicrobial peptides, some defensins are suppressors of ACTH activity on the mammalian adrenal cortex [56 ]. A similar inhibitory effect is that of neutrophil defensins on tissue-type plasminogen activator (tPA)-mediated fibrinolysis [57 ]. This inhibition may be part of the overall host defense function of defensins, in that prevention of clot dissolution by tPA-mediated fibrinolysis may better contain the inflammation associated with the introduction of a pathogen. In addition, extracellular defensins, such as hBD2, exhibit chemotactic activity for monocytes [58 ], immature dendritic cells (DC) [59 ], and T cells [60 ], suggestive of a pro-inflammatory activity. The chemotactic activity for DC and T cells appears to be mediated through the CCR6 receptor [59 ]. Defensins were also observed to be mitogenic for fibroblasts [61 ]. Together, these functions can be seen as a combined host defense system by linking direct bactericidal activity with recruitment of inflammatory cells and wound healing.


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SUMMARY
 
From gene structure to gene and tissue expression, it is evident that many homologies exist between mammalian defensins. These likenesses have been fundamental in uncovering new defensins from novel tissues and animals. However, marked differences also exist and have been reported in this review. Some defensins are constitutively expressed, whereas others are inducible. Not all defensins are expressed in all tissue types, and tissues that express numerous defensins do not express them at equal levels. Some defensins are inducible in one tissue type but not in another and yet some have roles outside the scope of antimicrobial activity. These observations suggest that the induction of defensin genes results in a myriad of effects, not limited to direct antimicrobial activity, but whose ultimate goal is the limitation of pathogenic infections. Analysis of tissue function differences both within and between species can contribute to understanding the molecular roles and evolutionary lineage of defensins.


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  		Table 2. Mammalian ß-Defensins


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ACKNOWLEDGEMENTS
 
The authors thank Danielle Laube and Diana Legarda for their helpful comments. G. D. was supported by grants from the National Heart Lung and Blood Institute (HL56400) and the Cystic Fibrosis Foundation (Diamon97P0).

Received August 13, 2000; revised August 21, 2000; accepted August 22, 2000.


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