Skip to main content
NCBI home page
The Journal of Cell Biology logoLink to The Journal of Cell Biology
. 1992 Aug 2;118(4):929–936. doi: 10.1083/jcb.118.4.929

Enteric defensins: antibiotic peptide components of intestinal host defense

PMCID: PMC2289569  PMID: 1500431

Abstract

Five intestinal defensins, termed cryptdins 1-5, have been purified from mouse small bowel, sequenced, and localized to the epithelium by immunohistochemistry. Although identified as members of the defensin peptide family by peptide sequencing, enteric defensins are novel in that four cryptdins have amino termini which are three to six residues longer than those of leukocyte-derived defensins. A fifth cryptdin is the first defensin to diverge from the previously invariant spacing of cysteines in the peptide structure. The most abundant enteric defensin, cryptdin-1, had antimicrobial activity against an attenuated phoP mutant of Salmonella typhimurium but was not active against the virulent wild-type parent. Immunohistochemical localization demonstrated that cryptdin-1, and probably cryptdins 2 and 3, occur exclusively in Paneth cells, where the peptides appear to be associated with cytoplasmic granules. Biochemical and immunologic analysis of the luminal contents of the small intestine suggest that cryptdin peptides are secreted into the lumen, similar to Paneth cell secretion of lysozyme. The presence of several enteric defensins in the intestinal epithelium, evidence of their presence in the lumen, and the antibacterial activity of cryptdin-1 suggest that these peptides contribute to the antimicrobial barrier function of the small bowel mucosa.

Full Text

The Full Text of this article is available as a PDF (4.1 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bjerknes M., Cheng H. The stem-cell zone of the small intestinal epithelium. I. Evidence from Paneth cells in the adult mouse. Am J Anat. 1981 Jan;160(1):51–63. doi: 10.1002/aja.1001600105. [DOI] [PubMed] [Google Scholar]
  2. Cheng H., Merzel J., Leblond C. P. Renewal of Paneth cells in the small intestine of the mouse. Am J Anat. 1969 Dec;126(4):507–525. doi: 10.1002/aja.1001260409. [DOI] [PubMed] [Google Scholar]
  3. Daher K. A., Lehrer R. I., Ganz T., Kronenberg M. Isolation and characterization of human defensin cDNA clones. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7327–7331. doi: 10.1073/pnas.85.19.7327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Fields P. I., Groisman E. A., Heffron F. A Salmonella locus that controls resistance to microbicidal proteins from phagocytic cells. Science. 1989 Feb 24;243(4894 Pt 1):1059–1062. doi: 10.1126/science.2646710. [DOI] [PubMed] [Google Scholar]
  5. Ganz T. Extracellular release of antimicrobial defensins by human polymorphonuclear leukocytes. Infect Immun. 1987 Mar;55(3):568–571. doi: 10.1128/iai.55.3.568-571.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ganz T., Rayner J. R., Valore E. V., Tumolo A., Talmadge K., Fuller F. The structure of the rabbit macrophage defensin genes and their organ-specific expression. J Immunol. 1989 Aug 15;143(4):1358–1365. [PubMed] [Google Scholar]
  7. Ganz T., Selsted M. E., Lehrer R. I. Defensins. Eur J Haematol. 1990 Jan;44(1):1–8. doi: 10.1111/j.1600-0609.1990.tb00339.x. [DOI] [PubMed] [Google Scholar]
  8. Ganz T., Selsted M. E., Szklarek D., Harwig S. S., Daher K., Bainton D. F., Lehrer R. I. Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest. 1985 Oct;76(4):1427–1435. doi: 10.1172/JCI112120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hammer M. F., Schilling J. W., Prager E. M., Wilson A. C. Recruitment of lysozyme as a major enzyme in the mouse gut: duplication, divergence, and regulatory evolution. J Mol Evol. 1987;24(3):272–279. doi: 10.1007/BF02111240. [DOI] [PubMed] [Google Scholar]
  10. Hill C. P., Yee J., Selsted M. E., Eisenberg D. Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization. Science. 1991 Mar 22;251(5000):1481–1485. doi: 10.1126/science.2006422. [DOI] [PubMed] [Google Scholar]
  11. Kagan B. L., Selsted M. E., Ganz T., Lehrer R. I. Antimicrobial defensin peptides form voltage-dependent ion-permeable channels in planar lipid bilayer membranes. Proc Natl Acad Sci U S A. 1990 Jan;87(1):210–214. doi: 10.1073/pnas.87.1.210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kent S. B. Chemical synthesis of peptides and proteins. Annu Rev Biochem. 1988;57:957–989. doi: 10.1146/annurev.bi.57.070188.004521. [DOI] [PubMed] [Google Scholar]
  13. Keshav S., Lawson L., Chung L. P., Stein M., Perry V. H., Gordon S. Tumor necrosis factor mRNA localized to Paneth cells of normal murine intestinal epithelium by in situ hybridization. J Exp Med. 1990 Jan 1;171(1):327–332. doi: 10.1084/jem.171.1.327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lehrer R. I., Barton A., Daher K. A., Harwig S. S., Ganz T., Selsted M. E. Interaction of human defensins with Escherichia coli. Mechanism of bactericidal activity. J Clin Invest. 1989 Aug;84(2):553–561. doi: 10.1172/JCI114198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lehrer R. I., Ganz T., Selsted M. E. Defensins: endogenous antibiotic peptides of animal cells. Cell. 1991 Jan 25;64(2):229–230. doi: 10.1016/0092-8674(91)90632-9. [DOI] [PubMed] [Google Scholar]
  16. Lehrer R. I., Rosenman M., Harwig S. S., Jackson R., Eisenhauer P. Ultrasensitive assays for endogenous antimicrobial polypeptides. J Immunol Methods. 1991 Mar 21;137(2):167–173. doi: 10.1016/0022-1759(91)90021-7. [DOI] [PubMed] [Google Scholar]
  17. Miller S. I., Kukral A. M., Mekalanos J. J. A two-component regulatory system (phoP phoQ) controls Salmonella typhimurium virulence. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5054–5058. doi: 10.1073/pnas.86.13.5054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Miller S. I. PhoP/PhoQ: macrophage-specific modulators of Salmonella virulence? Mol Microbiol. 1991 Sep;5(9):2073–2078. doi: 10.1111/j.1365-2958.1991.tb02135.x. [DOI] [PubMed] [Google Scholar]
  19. Miller S. I., Pulkkinen W. S., Selsted M. E., Mekalanos J. J. Characterization of defensin resistance phenotypes associated with mutations in the phoP virulence regulon of Salmonella typhimurium. Infect Immun. 1990 Nov;58(11):3706–3710. doi: 10.1128/iai.58.11.3706-3710.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ouellette A. J., Cordell B. Accumulation of abundant messenger ribonucleic acids during postnatal development of mouse small intestine. Gastroenterology. 1988 Jan;94(1):114–121. doi: 10.1016/0016-5085(88)90618-x. [DOI] [PubMed] [Google Scholar]
  21. Ouellette A. J., Lualdi J. C. A novel mouse gene family coding for cationic, cysteine-rich peptides. Regulation in small intestine and cells of myeloid origin. J Biol Chem. 1990 Jun 15;265(17):9831–9837. [PubMed] [Google Scholar]
  22. Ouellette A. J., Miller S. I., Henschen A. H., Selsted M. E. Purification and primary structure of murine cryptdin-1, a Paneth cell defensin. FEBS Lett. 1992 Jun 15;304(2-3):146–148. doi: 10.1016/0014-5793(92)80606-h. [DOI] [PubMed] [Google Scholar]
  23. Ouellette A. J., Pravtcheva D., Ruddle F. H., James M. Localization of the cryptdin locus on mouse chromosome 8. Genomics. 1989 Aug;5(2):233–239. doi: 10.1016/0888-7543(89)90051-7. [DOI] [PubMed] [Google Scholar]
  24. Pardi A., Hare D. R., Selsted M. E., Morrison R. D., Bassolino D. A., Bach A. C., 2nd Solution structures of the rabbit neutrophil defensin NP-5. J Mol Biol. 1988 Jun 5;201(3):625–636. doi: 10.1016/0022-2836(88)90643-2. [DOI] [PubMed] [Google Scholar]
  25. Peeters T., Vantrappen G. The Paneth cell: a source of intestinal lysozyme. Gut. 1975 Jul;16(7):553–558. doi: 10.1136/gut.16.7.553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pulkkinen W. S., Miller S. I. A Salmonella typhimurium virulence protein is similar to a Yersinia enterocolitica invasion protein and a bacteriophage lambda outer membrane protein. J Bacteriol. 1991 Jan;173(1):86–93. doi: 10.1128/jb.173.1.86-93.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. SPEECE A. J. HISTOCHEMICAL DISTRIBUTION OF LYSOZYME ACTIVITY IN ORGANS OF NORMAL MICE AND RADIATION CHIMERAS. J Histochem Cytochem. 1964 May;12:384–391. doi: 10.1177/12.5.384. [DOI] [PubMed] [Google Scholar]
  28. Satoh Y., Ishikawa K., Oomori Y., Yamano M., Ono K. Effects of cholecystokinin and carbamylcholine on Paneth cell secretion in mice: a comparison with pancreatic acinar cells. Anat Rec. 1989 Oct;225(2):124–132. doi: 10.1002/ar.1092250207. [DOI] [PubMed] [Google Scholar]
  29. Selsted M. E., Harwig S. S. Determination of the disulfide array in the human defensin HNP-2. A covalently cyclized peptide. J Biol Chem. 1989 Mar 5;264(7):4003–4007. [PubMed] [Google Scholar]
  30. Selsted M. E., Harwig S. S. Purification, primary structure, and antimicrobial activities of a guinea pig neutrophil defensin. Infect Immun. 1987 Sep;55(9):2281–2286. doi: 10.1128/iai.55.9.2281-2286.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Sparkes R. S., Kronenberg M., Heinzmann C., Daher K. A., Klisak I., Ganz T., Mohandas T. Assignment of defensin gene(s) to human chromosome 8p23. Genomics. 1989 Aug;5(2):240–244. doi: 10.1016/0888-7543(89)90052-9. [DOI] [PubMed] [Google Scholar]
  32. Staley M. W., Trier J. S. Morphologic heterogeneity of mouse Paneth cell granules before and after secretory stimulation. Am J Anat. 1965 Nov;117(3):365–383. doi: 10.1002/aja.1001170305. [DOI] [PubMed] [Google Scholar]
  33. Troughton W. D., Trier J. S. Paneth and goblet cell renewal in mouse duodenal crypts. J Cell Biol. 1969 Apr;41(1):251–268. doi: 10.1083/jcb.41.1.251. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Cell Biology are provided here courtesy of The Rockefeller University Press

RESOURCES