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PubMed2006

Neutrophil antimicrobial peptide alpha-defensin causes endothelial dysfunction in porcine coronary arteries.

BACKGROUND: Defensins are cysteine-rich cationic polypeptides released from neutrophils that exhibit powerful antimicrobial activities. Because inflammation, including neutrophil infiltration and release of defensins, may play an important role in atherosclerosis and other vascular diseases, we determined whether alpha-defensin could cause endothelial dysfunction, a major initial event of atherosclerosis, in porcine coronary arteries. METHODS: Porcine coronary arteries were sliced into 5-mm rings and treated with different concentrations of human recombinant alpha-defensin for 24 hours. Vasomotor reactivity was studied by using a myograph system. Levels of superoxide anion were detected by the lucigenin-enhanced chemiluminescence method. Endothelial nitric oxide synthase (eNOS) messenger RNA (mRNA) and protein levels were determined by real-time polymerase chain reaction and immunohistochemistry analysis, respectively. RESULTS: Endothelium-dependent relaxation in response to bradykinin was significantly reduced by 40% for the rings treated with 1500 nM of alpha-defensin compared with controls (P< .05). Vessel contractility in response to the thromboxane A2 analogue U46619 and endothelium-independent relaxation in response to sodium nitroprusside were not affected with defensin treatment. In addition, the superoxide anion level at the endothelial layer of porcine coronary artery rings was significantly increased by 80% in the defensin-treated (1500 nM) vessels compared with controls (P< .05). Furthermore, the eNOS mRNA levels in endothelial cells isolated from the cultured rings treated with defensin (1500 nM) were significantly decreased by 27% compared with controls (P< .05). Immunoreactivity of eNOS in the defensin-treated vessel rings was also substantially reduced. CONCLUSIONS: Defensin reduces the endothelium-dependent vasorelaxation. This effect is associated with increased superoxide radical production and decreased eNOS expression in porcine coronary arteries. CLINICAL RELEVANCE: Inflammation is an important mechanism of atherosclerosis and other vascular diseases. The roles and interactions of biomediators released from inflammatory cells are not fully understood, however. This study provides new information about effects and potential molecular mechanisms of a major neutrophil releasing factor, alpha-defensin, on endothelial dysfunction of porcine coronary arteries. Thus, targeting alpha-defensin and its associated molecular mechanisms may become a new strategy to prevent vascular diseases.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1998

Defensin gene expression in the cornea.

PURPOSE: To determine whether defensin genes are expressed in human corneas and bovine corneal keratocytes. METHODS: In situ hybridization and immunohistochemistry were used to localize defensin mRNA and protein in normal and diseased human corneas. Cultured bovine keratocytes were stimulated with IL-1alpha or TNFalpha to determine whether defensin mRNA production occurred. Reverse transcription polymerase chain reaction (RT-PCR) was performed to amplify defensin cDNA from cytokine-induced keratocytes, and Southern blots were used to verify the specificity of RT-PCR amplification products. RESULTS: Defensin mRNA and protein were not detected in normal human corneal stroma, but were readily detectable in the corneal stroma in cases of rejected transplants and postinfectious keratitis. IL-1alpha was a potent inducer of defensin gene expression in keratocytes, which began 12 h after challenge and peaked at 18 to 24 h. TNFalpha weakly induced defensin mRNA in keratocytes at about 18 h. Southern blots of the RT-PCR products probed with an oligonucleotide complementary to internal sequences of defensin demonstrated the appropriately sized products (198 bp) specific for defensin. CONCLUSIONS: This report demonstrates the presence of defensin in the human cornea and the capacity of corneal keratocytes to produce defensin mRNA in response to IL-1alpha and TNFalpha. Release of defensins by keratocytes in response to cytokines elaborated in corneal inflammation may contribute to the host defense response in microbial keratitis.

Animals↗
PubMed2003

alpha-Defensins can have anti-HIV activity but are not CD8 cell anti-HIV factors.

BACKGROUND: CD8 T cells from healthy HIV-infected individuals inhibit HIV replication in infected CD4 T cells by a non-cytotoxic mechanism mediated by a soluble CD8 cell antiviral factor, CAF. Recently, the antimicrobial peptides, alpha-defensins, were reported to constitute CAF. OBJECTIVE: To examine the antiviral activity of alpha-defensins and address their potential role in CD8 cell non-cytotoxic antiviral responses. DESIGN AND METHODS: A purified mixture of human neutrophil proteins (HNP) 1-3 (alpha-defensins) was used to examine the effect of alpha-defensins on HIV virions and on HIV replication in CD4 cells treated prior to or post infection. alpha-Defensin expression was analyzed at the RNA and protein level in CD8 cells as well as in various other cell types. Antibodies to the defensins were tested for their ability to inhibit CAF activity in CD8 cell culture fluids. RESULTS: The alpha-defensins exhibited anti-HIV activity on at least two levels: directly inactivating virus particles; and affecting the ability of target CD4 cells to replicate the virus. However, while we could demonstrate alpha-defensins in neutrophils and monocytes, we found no evidence for the production of these peptides by CD8 T cells. No messenger RNA encoding these proteins was detected in purified CD8 T cells, nor did these cells produce intracellular or extracellular alpha-defensin peptides. Moreover, antibodies specific for human alpha-defensins 1, 2, and 3 did not block the antiviral activity of CAF-active CD8 cell culture fluids. CONCLUSIONS: The alpha-defensins are not produced by CD8 cells but unexpectedly were found to be expressed in monocytes. alpha-Defensins can have anti-HIV activity but are not CD8 cell antiviral factors.

Antiviral Agents↗
PubMed2007

Multispecific myeloid defensins.

PURPOSE OF REVIEW: This review describes recent progress in our understanding of defensins and their contributions to innate immunity. Defensins are small, cysteine-rich endogenous antibiotic peptides. Human neutrophils contain large amounts of three alpha-defensins (HNP-1-HNP-3), and smaller amounts of a fourth, HNP-4. Monocytes and macrophages generally lack defensins, but they release messengers that induce the synthesis of beta-defensins in epithelial cells. RECENT FINDINGS: In addition to their antimicrobial and immunomodulatory effects, HNP-1-HNP-3 possess antiviral and toxin-neutralizing properties. Induction of beta-defensins in epithelial cells is mediated by cell-surface Toll-like receptors or cytoplasmic peptidoglycan receptors that can recognize pathogen-associated molecules. Mutations in Nod2, a cytoplasmic peptidoglycan receptor, are associated with reduced levels of intestinal alpha-defensins and ileal Crohn's disease. Human defensin genes show marked copy-number polymorphism. High level constitutive expression of defensins may afford protection against HIV-1 and other defensin-sensitive pathogens. Theta-defensins (cyclic octadecapeptides found in nonhuman primates) have impressive antiviral and antitoxic properties. SUMMARY: The multiple properties of defensins contribute to human innate immunity against bacteria, bacterial toxins, and viruses.

Animals↗
PubMed1999

Antimicrobial defensin peptides of the human ocular surface.

BACKGROUND/AIMS: The antimicrobial activity of the tear film exceeds the activity of its known constituents. The authors postulate that this excess activity is the result of antimicrobial peptides called defensins, and they aimed to look for defensins in the human eye. METHODS: Evidence of defensin production was sought by reverse transcriptase polymerase chain reaction (RT-PCR). Intron spanning primers were designed for beta defensins 1 and 2, and alpha defensins 5 and 6. RT-PCR was performed on cornea, conjunctiva, and lacrimal gland samples, and reaction products were size fractionated and sequenced to confirm their identity. A monoclonal antibody was utilised for the detection of alpha defensins 1, 2, and 3 in tissue sections and in immunoblots of tears. RESULTS: RT-PCR revealed beta defensin 1 message in samples of conjunctiva, cornea, and lacrimal gland. beta Defensin 2 message was detected in the conjunctiva and cornea but was absent from the lacrimal gland. alpha Defensin 5 and 6 message was absent in these tissues but alpha defensins 1, 2, and 3 were detected in normal tears, lacrimal gland, and inflamed conjunctiva by immunochemistry. CONCLUSION: The data suggest the human eye innately produces a spectrum of antimicrobial defensin peptides. Defensins hold therapeutic potential in ocular infections as they have a broad spectrum of antimicrobial activity (bacteria fungi and viruses ) and accelerate epithelial healing.

Conjunctiva↗
PubMed2005

Dual role of alpha-defensin-1 in anti-HIV-1 innate immunity.

Alpha-defensins are abundant antimicrobial peptides in polymorphonuclear leukocytes and play an important role in innate immunity. We have previously shown that alpha-defensin-1 can inhibit HIV-1 replication following viral entry. Here we examined the molecular mechanism(s) of alpha-defensin-1-mediated HIV-1 inhibition. Alpha-defensin-1 had a direct effect on HIV-1 virions at a low MOI in the absence of serum. The direct effect on HIV-1 virions was abolished by the presence of serum or an increase in virus particles. Studying the kinetics of the HIV life cycle revealed that alpha-defensin-1 inhibited steps following reverse transcription and integration. Analysis of PKC phosphorylation in primary CD4+ T cells in response to alpha-defensin-1 indicated that alpha-defensin-1 inhibited PKC activity. Pretreatment of infected CD4+ T cells with a PKC activator, bryostatin 1, partially reversed alpha-defensin-1-mediated HIV inhibition. Like alpha-defensin-1, the PKC isoform-selective inhibitor Go6976 blocked HIV-1 infection in a dose-dependent manner. Furthermore, kinetic studies and analysis of HIV-1 products indicated that alpha-defensin-1 and Go6976 blocked HIV-1 infection at similar stages in its life cycle, including nuclear import and transcription. Taken together, our studies demonstrate that, in the absence of serum, alpha-defensin-1 may act directly on the virus, but, in the presence of serum, its effects are on the cell, where it inhibits HIV-1 replication. At least 1 of the cellular effects associated with HIV inhibition is interference with PKC signaling in primary CD4+ T cells. Studying the complex function of alpha-defensin-1 in innate immunity against HIV has implications for prevention as well as therapeutics.

Antiviral Agents↗
PubMed2002

Antimicrobial defensin peptides of the human nasal mucosa.

Defensins, a prominent group of antimicrobial peptides, are an important component of the innate immune response, particularly at mucosal surfaces that are vulnerable to colonization by potential pathogens. The present study was undertaken to investigate the expression of defensins in inferior turbinate mucosa of normal subjects and inferior turbinate mucosa and nasal polyps of patients with chronic sinusitis. Expression of beta-defensin 1 and 2 and alpha-defensin 5 and 6 messenger RNAs (mRNAs) was investigated by reverse transcriptase-polymerase chain reaction, and their expression level was semiquantitatively evaluated by dot blot hybridization. Immunohistochemical analysis was used for detection of alpha-defensins 1, 2, and 3 in tissue sections. Beta-defensin 1 mRNA was expressed in all tissue samples, at levels that did not differ significantly. Beta-defensin 2 mRNA was detected in the turbinate mucosa and nasal polyps of patients with chronic sinusitis, but not in normal mucosa. Its expression level was significantly higher in nasal polyps than in turbinate mucosa. Alpha-defensin 5 and 6 mRNAs were not expressed in any tissues, but alpha-defensins 1, 2, and 3 were detected in all tissue samples obtained from patients with chronic sinusitis. These results suggest that beta-defensin 1 may play a constitutive role in nasal defenses, whereas alpha-defensins 1, 2, and 3 and beta-defensin 2 may be induced in response to local infection or inflammation.

Adult↗
PubMed2002

Human alpha-defensin regulates smooth muscle cell contraction: a role for low-density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor.

We have previously identified alpha-defensin in association with medial smooth muscle cells (SMCs) in human coronary arteries. In the present paper we report that alpha-defensin, at concentrations below those found in pathological conditions, inhibits phenylephrine (PE)-induced contraction of rat aortic rings. Addition of 1 microM alpha-defensin increased the half-maximal effective concentration (EC(50)) of PE on denuded aortic rings from 32 to 630 nM. The effect of alpha-defensin was dose dependent and saturable, with a half-maximal effect at 1 microM. alpha-Defensin binds to human umbilical vein SMCs in a specific manner. The presence of 1 microM alpha-defensin inhibited the PE-mediated Ca(++) mobilization in SMCs by more than 80%. The inhibitory effect of alpha-defensin on contraction of aortic rings and Ca(++) mobilization was completely abolished by anti-low-density lipoprotein receptor-related protein/alpha(2-)macroglobulin receptor (LRP) antibodies as well as by the antagonist receptor-associated protein (RAP). alpha-Defensin binds directly to isolated LRP in a specific and dose-dependent manner; the binding was inhibited by RAP as well as by anti-LRP antibodies. alpha-Defensin is internalized by SMCs and interacts with 2 intracellular subtypes of protein kinase C (PKC) involved in muscle contraction, alpha and beta. RAP and anti-LRP antibodies inhibited the binding and internalization of alpha-defensin by SMCs and its interaction with intracellular PKCs. These observations suggest that binding of alpha-defensin to LRP expressed in SMCs leads to its internalization; internalized alpha-defensin binds to PKC and inhibits its enzymatic activity, leading to decreased Ca(++) mobilization and SMC contraction in response to PE.

Animals↗
PubMed2004

Staphylococcus aureus resists human defensins by production of staphylokinase, a novel bacterial evasion mechanism.

Alpha-defensins are peptides secreted by polymorphonuclear cells and provide antimicrobial protection mediated by disruption of the integrity of bacterial cell walls. Staphylokinase is an exoprotein produced by Staphylococcus aureus, which activates host plasminogen. In this study, we analyzed the impact of interaction between alpha-defensins and staphylokinase on staphylococcal growth. We observed that staphylokinase induced extracellular release of alpha-defensins from polymorphonuclear cells. Moreover, a direct binding between alpha-defensins and staphylokinase was shown to result in a complex formation. The biological consequence of this interaction was an almost complete inhibition of the bactericidal effect of alpha-defensins. Notably, staphylokinase with blocked plasminogen binding site still retained its ability to neutralize the bactericidal effect of alpha-defensins. In contrast, a single mutation of a staphylokinase molecule at position 74, substituting lysine for alanine, resulted in a 50% reduction of its alpha-defensin-neutralizing properties. The bactericidal properties of alpha-defensins were tested in 19 S. aureus strains in vitro and in a murine model of S. aureus arthritis. Staphylococcal strains producing staphylokinase were protected against the bactericidal effect of alpha-defensins. When staphylokinase was added to staphylokinase-negative S. aureus cultures, it almost totally abrogated the effect of alpha-defensins. Finally, human neutrophil peptide 2 injected intra-articularly along with bacteria alleviated joint destruction. In this study, we report a new property of staphylokinase, its ability to induce secretion of defensins, to complex bind them and to neutralize their bactericidal effect. Staphylokinase production may therefore be responsible in vivo for defensin resistance during S. aureus infections.

Adult↗
PubMed1990

Characterization of defensin resistance phenotypes associated with mutations in the phoP virulence regulon of Salmonella typhimurium.

The defensin sensitivities of Salmonella typhimurium strains with mutations in the phoP/phoQ two-component virulence regulon were tested by using purified defensins NP-1 and NP-2. Strains with mutations in either gene of the regulatory pair (phoP [transcriptional activator] or phoQ [membrane sensor kinase]) had increased sensitivities to defensin. The predicted periplasmic domain of the PhoQ protein contained a markedly anionic domain that could interact with cationic proteins and that could be responsible for resistance to defensin. Because insertion mutations in phoP are polar on phoQ, we constructed strains that expressed the PhoQ protein in the absence of PhoP to test whether resistance to defensin requires only the phoQ gene product. We found that resistance to defensin requires the function of both components of this regulatory system, because strains expressing PhoQ without PhoP were still markedly sensitive to defensins. This implied that a pag (phoP-activated gene) product is responsible for defensin resistance. We also tested for the ability of defensins NP-1, NP-5, and HNP-1 to activate pag expression and found that these peptides have no effect. Defensin resistance is not the only virulence characteristic controlled by the PhoP-PhoQ regulon because mutations in pagC, as well as ones in the phoP locus that resulted in constitutive pag activation (phenotype PhoPc), had no effect on defensin resistance, even though they rendered the organism avirulent and deficient in survival within macrophages. The virulence defect conferred by mutations in the phoP-phoQ two-component regulatory system is not completely explained by alterations in resistance to cationic proteins and involves the control of other proteins necessary for S. typhimurium survival within macrophages.

Animals↗
PubMed1999

Molecular cloning and characterization of rat genes encoding homologues of human beta-defensins.

beta-Defensins are cationic peptides with broad-spectrum antimicrobial activity that may play a role in mucosal defenses of several organs. They have been isolated in several species, and in humans, two beta-defensins have been identified. Here, we report the identification of two genes encoding beta-defensin homologues in the rat. Partial cDNAs were found by searching the expressed-sequence-tag database, and primers were designed to generate full-length mRNA coding sequences. One gene was highly similar to the human beta-defensin-1 (HBD-1) gene and mouse beta-defensin-1 gene at both the nucleic acid and amino acid levels and was termed rat beta-defensin-1 (RBD-1). The other gene, named RBD-2, was homologous to the HBD-2 and bovine tracheal antimicrobial peptide (TAP) genes. The predicted prepropeptides were strongly cationic, were 69 and 63 residues in length for RBD-1 and RBD-2, respectively, and contained the six-cysteine motif characteristic of beta-defensins. The beta-defensin genes mapped closely on rat chromosome 16 and were closely linked to the alpha-defensins genes, suggesting that they are part of a gene cluster, similar to the organization reported for humans. Northern blot analysis showed that both RBD-1 and RBD-2 mRNA transcripts were approximately 0.5 kb in length; RBD-1 mRNA was abundantly transcribed in the rat kidney, while RBD-2 was prevalent in the lung. Reverse transcription-PCR indicated that RBD-1 and RBD-2 mRNAs were distributed in a variety of other tissues. In the lung, RBD-1 mRNA expression localized to the tracheal epithelium while RBD-2 was expressed in alveolar type II cells. In conclusion, we characterized two novel beta-defensin homologues in the rat. The rat may be a useful model to investigate the function and contribution of beta-defensins to host defense in the lung, kidney, and other tissues.

Amino Acid Sequence↗
PubMed2005

Cross-species analysis of the mammalian beta-defensin gene family: presence of syntenic gene clusters and preferential expression in the male reproductive tract.

Mammalian beta-defensins are an important family of innate host defense peptides with pleiotropic activities. As a first step to study the evolutionary relationship and biological role of the beta-defensin family, we identified their complete repertoires in the human, chimpanzee, mouse, rat, and dog following systemic, genome-wide computational searches. Although most beta-defensin genes are composed of two exons separated by an intron of variable length, some contain an additional one or two exons encoding an internal pro-sequence, a segment of carboxy-terminal mature sequences or untranslated regions. Alternatively, spliced isoforms have also been found with several beta-defensins. Furthermore, all beta-defensin genes are densely clustered in four to five syntenic chromosomal regions, with each cluster spanning <1.2 Mb across the five species. Phylogenetic analysis indicated that, although the majority of beta-defensins are evolutionarily conserved across species, subgroups of gene lineages exist that are specific in certain species, implying that some beta-defensins originated after divergence of these mammals from each other, while most others arose before the last common ancestor of mammals. Surprisingly, RT-PCR revealed that all but one rat beta-defensin transcript are preferentially expressed in the male reproductive tract, particularly in epididymis and testis, except that Defb4, a human beta-defensin-2 ortholog, is more restricted to the respiratory and upper gastrointestinal tracts. Moreover, most beta-defensins expressed in the reproductive tract are developmentally regulated, with enhanced expression during sexual maturation. Existence of such a vast array of beta-defensins in the male reproductive tract suggests that these genes may play a dual role in both fertility and host defense.

Amino Acid Sequence↗
PubMed2004

Activity of alpha- and theta-defensins against primary isolates of HIV-1.

Theta-defensins are lectin-like, cyclic octadecapeptides found in the leukocytes of nonhuman primates. They are also homologues of the more familiar alpha-defensins expressed by humans and certain other mammals. This study compares the ability of six theta-defensins (hominid retrocyclins 1-3 and rhesus theta-defensins 1-3) and four human alpha-defensins (human neutrophil peptides (HNPs) 1-4) to bind gp120 and CD4. In addition, we compared the ability of these theta-defensins and HNP-1 to protect J53-BL cells (an indicator cell line) from primary HIV-1 isolates that varied in subtype and coreceptor usage. The most potent theta-defensin, retrocyclin-2, bound with exceptionally high affinity to gp120 (K(D), 9.4 nM) and CD4 (K(D), 6.87 nM), and its effectiveness against subtype B isolates (IC(50), 1.05 +/- 0.28 microg/ml; 520 +/- 139 nM) was approximately twice as great as that of HNP-1 on a molar basis. We also show, for the first time, that human alpha-defensins, HNPs 1-3, are lectins that bind with relatively high affinity to gp120 (K(D) range, 15.8-52.8 nM) and CD4 (K(D) range, 8.0-34.9 nM). Proteins found in human and FBS bound exogenous HNP-2 and retrocyclin-1, and competed with their ability to bind gp120. However, even the low concentrations of alpha-defensins found in normal human serum suffice to bind over half of the gp120 spikes on HIV-1 and a higher percentage of cell surface CD4 molecules. Although this report principally concerns the relationship between carbohydrate-binding and the antiviral properties of alpha- and theta-defensins, the lectin-like behavior of defensins may contribute to many other activities of these multifunctional peptides.

Amino Acid Sequence↗
PubMedDate not supplied

Expression of defensin antimicrobial peptides in the peritoneal cavity of patients on peritoneal dialysis.

OBJECTIVE: To investigate the expression and regulation of defensins in the peritoneal cavity of peritoneal dialysis (PD) patients. DESIGN: The presence of defensins in the peritoneal cavity was assessed using reverse transcription polymerase chain reaction (RT-PCR). In vivo defensin expression was analyzed in human peritoneal membrane biopsies and in peritoneal cavity leukocytes isolated from spent dialysate. Defensin expression in vitro was assessed in cultured human peritoneal mesothelial cells (HPMC) and confirmed with PCR Southern blot and DNA sequencing. The effect of tumor necrosis factor alpha (TNFalpha) and epidermal growth factor (EGF) on beta2 defensin expression in HPMC was analyzed by Northern blot analysis and RT-PCR respectively. RESULTS: Both alpha and beta classes of defensins are expressed in the peritoneal cavity of PD patients. Messenger RNA for the alpha-defensin human neutrophil peptide 3 and for beta-defensin-1 (hbetaD-1) were found in preparations containing predominantly peritoneal leukocytes, whereas beta-defensin-2 (hbetaD-2) is expressed by HPMC. HPMC isolated from different individuals displayed variability in both basal hbetaD-2 expression and in response to stimulation by TNFalpha. Conversely, EGF consistently downregulated the level of hbetaD-2 message in HPMC. CONCLUSION: Alpha- and beta-defensins are expressed in the peritoneal cavity, and hbetaD-2 is the main defensin present in the peritoneal membrane. Variable levels of expression of hbetaD-2 by mesothelial cells were seen, with evidence of regulation by cytokines and growth factors. This provides evidence for a previously unknown mechanism of innate immunity at that site.

Base Sequence↗
PubMed1999

Evolutionary diversification of the mammalian defensins.

Defensins are cysteine-rich cationic peptides that function in antimicrobial defense in both invertebrates and vertebrates. Three main groups of animal defensins are known: insect defensins; mammalian alpha-defensins and vertebrate beta-defensins. It has been difficult to determine whether these molecules are homologous or have independently evolved similar features, but overall the evidence favors a distant relationship. The best evidence of this relationship is structural, particularly from their overall three-dimensional structure and from the spacing of half-cystine residues involved in intra-chain disulfide bonds. Some evidence favors a closer relationship between vertebrate beta-defensins and insect defensins than between the two groups of vertebrate defensins. Examination of nucleotide substitutions between recently duplicated mammalian defensin genes shows that the rate of nonsynonymous (amino-acid-altering) substitution exceeds that of synonymous substitution in the region of the gene encoding the mature defensin. This highly unusual pattern of nucleotide substitution is evidence that natural selection has acted to diversify defensins at the amino acid level. The resulting rapid evolution explains why it is difficult to reconstruct the evolutionary history of these molecules.

Amino Acid Sequence↗
PubMed2005

Human defensins.

Antimicrobial peptides are small, cationic, amphiphilic peptides of 12-50 amino acids with microbicidal activity against both bacteria and fungi. The eukaryotic antimicrobial peptides may be divided into four distinct groups according to their structural features: cysteine-free alpha-helices, extended cysteine-free alpha-helices with a predominance of one or two amino acids, loop structures with one intramolecular disulfide bond, and beta-sheet structures which are stabilised by two or three intramolecular disulfide bonds. Mammalian defensins are part of the last-mentioned group. The mammalian defensins can be subdivided into three main classes according to their structural differences: the alpha-defensins, beta-defensins and the recently described theta-defensins. Mammalian alpha-defensins are predominantly found in neutrophils and in small intestinal Paneth cells, whereas mammalian beta-defensins have been isolated from both leukocytes and epithelial cells. Recently, two novel human beta-defensins, human beta-defensin-3 (HBD-3), and human beta-defensin-4 (HBD-4) have been discovered. Similar to HBD-1 and HBD-2, HBD-3 has microbicidal activity towards the Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli) and the yeasts Candida albicans and Malassezia furfur. In addition, HBD-3 kills Gram-positive bacteria such as Streptococcus pyogenes or Staphylococcus aureus, including multi-resistant S. aureus strains, and even vancomycin-resistant Enterococcus faecium. In contrast to HBD-1 and HBD-2, significant expression of HBD-3 has been demonstrated in non-epithelial tissues, such as leukocytes, heart and skeletal muscle. HBD-4 is expressed in certain epithelia and in neutrophils. Its bactericidal activity against P. aeruginosa is stronger than that of the other known beta-defensins. Here we present an overview of human antimicrobial peptides with some emphasis on their antifungal properties.

Animals↗
PubMed2002

Plant defensins.

Plant defensins are small, basic peptides that have a characteristic three-dimensional folding pattern that is stabilized by eight disulfide-linked cysteines. They are termed plant defensins because they are structurally related to defensins found in other types of organism, including humans. To date, sequences of more than 80 different plant defensin genes from different plant species are available. In Arabidopsis thaliana, at least 13 putative plant defensin genes (PDF) are present, encoding 11 different plant defensins. Two additional genes appear to encode plant defensin fusions. Plant defensins inhibit the growth of a broad range of fungi but seem nontoxic to either mammalian or plant cells. Antifungal activity of defensins appears to require specific binding to membrane targets. This review focuses on the classification of plant defensins in general and in Arabidopsis specifically, and on the mode of action of plant defensins against fungal pathogens.

Amino Acid Sequence↗
PubMedDate not supplied

Overexpression of alpha-defensin is associated with bladder cancer invasiveness.

Alpha-defensin (alpha-defensin) has been identified as a potential marker for bladder cancer in urine by surface enhanced laser desorption ionization studies, and confirmed using both immunoabsorption and immunodepletion studies. The objective of this study was to investigate the role of alpha-defensin in bladder cancer. Immunohistochemical analysis of tissue sections showed that alpha-defensin peptides are frequently expressed in bladder cancer cells. It is noteworthy that expression of alpha-defensins increased with tumor invasiveness. Surface enhanced laser desorption ionization analysis showed the presence of alpha-defensin in the T24 and A498 cancer cell lines. These cell lines show higher classically aggressive in vitro characteristics compared with the J82 cells that did not express alpha-defensin. Exogenously added alpha-defensin increased the proliferation and motility/invasiveness of these cell lines using respective assays. It is interesting that alpha-defensin peptides increased intracellular calcium ions (Ca2+). These data are consistent with a role for alpha-defensin in bladder cancer via modulation of cell motility and invasiveness using common intracellular signals, such as Ca2+. We propose that autocrine tumor expression of alpha-defensins may play an important role in facilitating the invasive phenotype of bladder cancer in patients.

Carcinoma, Transitional Cell↗