HGNC Approved Gene Symbol: DEFB1
Cytogenetic location: 8p23.1 Genomic coordinates (GRCh38): 8:6,870,592-6,877,936 (from NCBI)
The production of antimicrobial peptides by eukaryotic cells has been demonstrated in plants, invertebrates, and vertebrates, suggesting that it is a widespread and ancient means of host defense. In mammals, 2 seemingly distinct families of 3.5- to 5-kD cysteine- and arginine-rich antimicrobial peptides have been identified: alpha-defensins, found in phagocytes of human and other mammals and in Paneth cells of the small intestine of the human, mouse, and rat; and beta-defensins, located in bovine (and avian) phagocytes and bovine lingual and tracheal epithelia (Ganz and Lehrer, 1995). Liu et al. (1997) cloned a novel human beta-defensin gene and determined its full-length cDNA sequence. The 362-bp cDNA encodes a prepropeptide that corresponds precisely to the human beta-defensin HBD1, an antimicrobial peptide implicated in the resistance of epithelial surfaces to microbial colonization (Bensch et al., 1995). DEFB1 appears to be involved in the antimicrobial defense of epithelia of surfaces such as those of the respiratory tract, urinary tract, and vagina.
Morrison et al. (1998) found that the Defb1 gene was expressed in a variety of mouse tissues, including the airways and, similar to the human gene, was not upregulated by lipopolysaccharide (LPS). Like the human protein, the mouse defensin demonstrated a salt-sensitive antimicrobial activity against Pseudomonas aeruginosa. Of relevance to cystic fibrosis (CF; 219700) lung disease was the fact that neither the human nor the mouse peptides were active against Burkholderia cepacia.
Goldman et al. (1997) used a human bronchial xenograft model to characterize the molecular basis for the previously described defect in bacterial killing that is present in cystic fibrosis lung. Airway surface fluid from CF grafts contained abnormally high NaCl and failed to kill bacteria, defects that were corrected with adenoviral vectors. They found that the beta-defensin gene is expressed throughout the respiratory epithelia of non-CF and CF lungs, and that its protein product shows salt-dependent antimicrobial activity to P. aeruginosa. Antisense oligonucleotides to beta-defensin ablated the antimicrobial activity in airway surface fluid from non-CF grafts. These data suggested to Goldman et al. (1997) that beta-defensin plays an important role in innate immunity and that this role is compromised in CF by salt-dependent inactivation. They found that in the presence of low sodium chloride, synthetic beta-defensin demonstrated potent bactericidal activity to a broad array of organisms but showed a sharp loss of activity as the salt concentration increased.
By Northern blot analysis, Valore et al. (1998) found the highest concentrations of DEFB1 mRNA in the kidney and the female reproductive tract. In situ hybridization localized the DEFB1 mRNA in the epithelial layers of the loops of Henle, distal tubules, and collecting ducts of the kidney, and the epithelial layers of the vagina, ectocervix, endocervix, uterus, and fallopian tubes in the female reproductive tract. Using a novel technique designed to detect cationic peptides in urine, they recovered several forms of beta-defensin-1, ranging in length from 36 to 47 amino acid residues and differing from each other by amino terminal truncation. The total concentration of DEFB1 forms in voided urine was estimated to be 10 to 100 micro g/l, with individual variations in the total amount of DEFB1 peptides and the relative proportion of the DEFB1 forms. Multiple forms were also found in blood plasma, bound to carrier macromolecules that released the peptide under acid conditions, and in vaginal mucosal secretions. Recombinant DEFB1 forms and natural DEFB1 forms were antimicrobial in laboratory and clinical strains of E. coli at micromolar concentrations. Activity of the material was not changed appreciably by low pH, but was inhibited by high salt concentrations. Some of the DEFB1 peptides retained their activity against E. coli in unconcentrated (low conductance) urine, and the 36-amino acid form was microbicidal even in normal (high conductance) urine. Valore et al. (1998) concluded that production of beta-defensin-1 in the urogenital tract may contribute to local antimicrobial defense.
Singh et al. (1998) showed that DEFB1 and DEFB2 mRNAs are expressed in excised surface and submucosal gland epithelia from non-CF and CF patients. Interleukin-1-beta (IL1B; 147720) stimulated the expression of DEFB2 but not of DEFB1 mRNA and peptide in primary cultures of airway epithelia. Beta-defensin-1 was found in bronchoalveolar lavage (BAL) fluid from normal volunteers, CF patients, and patients with inflammatory lung diseases, whereas beta-defensin-2 was detected in BAL fluid from patients with CF or inflammatory lung diseases, but not in normal volunteers. Both beta-defensin-1 and beta-defensin-2 showed salt-sensitive bactericidal activity. These data suggested that expression of DEFB2 is induced in the lung by inflammation, whereas DEFB1 may serve as a defense in the absence of inflammation.
By RT-PCR, Tunzi et al. (2000) identified the DEFB1 transcript in a human mammary gland epithelial cell line, in mammary glandular tissue of 9 nonlactating women, and in epithelial cells harvested from milk of lactating women. Immunostaining confirmed the presence of DEFB1 peptide in mammary epithelia.
Jia et al. (2001) detected human beta-defensin-1 in breast milk at concentrations of approximately 1 to 10 microgram/ml. Breast tissue during lactation showed DEFB1 expression in mammary gland epithelia and within luminal secretions. The peptide demonstrated antimicrobial activity against E. coli. Jia et al. (2001) concluded that DEFB1 may augment neonatal host defenses through antimicrobial effects or prime the adaptive immune system at mucosal surfaces.
By in situ hybridization, immunocytochemical, and RT-PCR analyses, Duits et al. (2002) showed that DEFB1 and DEFB2 were expressed by monocytes and macrophages and that expression increased after activation with IFNG (147570) and/or LPS in a dose- and time-dependent manner. Expression of DEFB1, but not DEFB2, was detectable in dendritic cells and increased after dendritic cell maturation.
Schroeder et al. (2011) showed that after reduction of disulfide bridges, human DEFB1 becomes a potent antimicrobial peptide against the opportunistic pathogenic fungus Candida albicans and against anaerobic, gram-positive commensals of Bifidobacterium and Lactobacillus species. Reduced human DEFB1 differs structurally from oxidized DEFB1, and free cysteines in the carboxy terminus seem important for the bactericidal effect. In vitro, the thioredoxin system (see 187700) is able to reduce DEFB1, and thioredoxin colocalizes with reduced DEFB1 in human epithelia. Schroeder et al. (2011) concluded that reduced DEFB1 shields the healthy epithelium against colonization by commensal bacteria and opportunistic fungi. Accordingly, an intimate interplay between redox regulation and innate immune defense seems crucial for an effective barrier protecting human epithelia.
Liu et al. (1997) determined that the DEFB1 gene spans more than 7 kb and includes a large 6,962-bp intron.
Morrison et al. (1998) determined that the mouse Defb1 gene consists of 2 small exons separated by a 16-kb intron.
By 2-color fluorescence in situ hybridization on both metaphase chromosomes and released chromatin fiber, Liu et al. (1997) mapped the DEFB1 gene to 8p23.2-p23.1, within 100 to 150 kb of the gene for human neutrophil defensin-alpha-1 (125220). Huttner et al. (1997) demonstrated that the mouse homolog maps to chromosome 8 at or near the location of the mouse alpha-defensin genes.
Bensch, K. W., Raida, M., Magert, H. J., Schulz-Knappe, P., Forssmann, W. G. hBD-1: a novel beta-defensin from human plasma. FEBS Lett. 368: 331-335, 1995. [PubMed: 7628632] [Full Text: https://doi.org/10.1016/0014-5793(95)00687-5]
Duits, L. A., Ravensbergen, B., Rademaker, M., Hiemstra, P. S., Nibbering, P. H. Expression of beta-defensin 1 and 2 mRNA by human monocytes, macrophages and dendritic cells. Immunology 106: 517-525, 2002. [PubMed: 12153515] [Full Text: https://doi.org/10.1046/j.1365-2567.2002.01430.x]
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Goldman, M. J., Anderson, G. M., Stolzenberg, E. D., Kari, U. P., Zasloff, M., Wilson, J. M. Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell 88: 553-560, 1997. [PubMed: 9038346] [Full Text: https://doi.org/10.1016/s0092-8674(00)81895-4]
Huttner, K. M., Kozak, C. A., Bevins, C. L. The mouse genome encodes a single homolog of the antimicrobial peptide human beta-defensin 1. FEBS Lett. 413: 45-49, 1997. [PubMed: 9287114] [Full Text: https://doi.org/10.1016/s0014-5793(97)00875-2]
Jia, H. P., Starner, T., Ackermann, M., Kirby, P., Tack, B. F., McCray, P. B., Jr. Abundant human beta-defensin-1 expression in milk and mammary gland epithelium. J. Pediat. 138: 109-112, 2001. [PubMed: 11148522] [Full Text: https://doi.org/10.1067/mpd.2001.109375]
Liu, L., Zhao, C., Heng, H. H. Q., Ganz, T. The human beta-defensin-1 and alpha-defensins are encoded by adjacent genes: two peptide families with differing disulfide topology share a common ancestry. Genomics 43: 316-320, 1997. [PubMed: 9268634] [Full Text: https://doi.org/10.1006/geno.1997.4801]
Morrison, G. M., Davidson, D. J., Kilanowski, F. M., Borthwick, D. W., Crook, K., Maxwell, A. I., Govan, J. R. W., Dorin, J. R. Mouse beta defensin-1 is a functional homolog of human beta defensin-1. Mammalian Genome 9: 453-457, 1998. [PubMed: 9585433] [Full Text: https://doi.org/10.1007/s003359900795]
Schroeder, B. O., Wu, Z., Nuding, S., Groscurth, S., Marcinowski, M., Beisner, J., Buchner, J., Schaller, M., Stange, E. F., Wehkamp, J. Reduction of disulphide bonds unmasks potent antimicrobial activity of human beta-defensin 1. Nature 469: 419-423, 2011. [PubMed: 21248850] [Full Text: https://doi.org/10.1038/nature09674]
Singh, P. K., Jia, H. P., Wiles, K., Hesselberth, J., Liu, L., Conway, B.-A. D., Greenberg, E. P., Valore, E. V., Welsh, M. J., Ganz, T., Tack, B. F., McCray, P. B., Jr. Production of beta-defensins by human airway epithelia. Proc. Nat. Acad. Sci. 95: 14961-14966, 1998. Note: Erratum: Proc. Nat. Acad. Sci. 96: 2569 only, 1999. [PubMed: 9843998] [Full Text: https://doi.org/10.1073/pnas.95.25.14961]
Tunzi, C. R., Harper, P. A., Bar-Oz, B., Valore, E. V., Semple, J. L., Watson-MacDonell, J., Ganz, T., Ito, S. Beta-defensin expression in human mammary gland epithelia. Pediat. Res. 48: 30-35, 2000. [PubMed: 10879797] [Full Text: https://doi.org/10.1203/00006450-200007000-00008]
Valore, E. V., Park, C. H., Quayle, A. J., Wiles, K. R., McCray, P. B., Jr., Ganz, T. Human beta-defensin-1: an antimicrobial peptide of urogenital tissues. J. Clin. Invest. 101: 1633-1642, 1998. [PubMed: 9541493] [Full Text: https://doi.org/10.1172/JCI1861]