Chapter 12 : Antimicrobial Peptide Effectors of Small Intestinal Innate Immunity

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This chapter deals with and reviews evidence that α-defensins secreted by mucosal Paneth cells contribute to innate immunity against bacteria in the small intestine. Growing experimental evidence has led to acceptance of the concept that species produce antimicrobial peptides constitutively or inducibly in response to infection. In mammals, antimicrobial proteins and peptide genes are expressed by varied differentiated cell lineages, including epithelial cells and phagocytes. The α-defensins are major constituents of azurophilic granules in mammalian phagocytic leukocytes, and they are released by a limited number of epithelial cell lineages. The α-defensins from human and rabbit neutrophils achieve bacterial cell killing by distinctive membrane disruptive mechanisms. Acquired immune responses to infectious agents mediated by T cells and B cells are initiated by specific antigens and are selective, but lymphocytic responses may not be rapid enough to contain acute infections by rapidly growing microorganisms or by pathogens that infect a naive host. Absorptive enterocytes, goblet cells, and Paneth cells of the small intestine elaborate lineage-specific gene products or exhibit activities that contribute to enteric host defense. Paneth cell granules are rich in antibiotic proteins and peptides, and release of these granules contributes to mucosal defense. Paneth cells emerge during cytodifferentiation of the fetal small intestinal endoderm from an intervillous epithelium that leads to cryptontogeny. The inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, have provided links between altered mucosal barrier function and the intestinal microflora.

Citation: Ouellette A, Selsted M. 2003. Antimicrobial Peptide Effectors of Small Intestinal Innate Immunity, p 191-221. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch12

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Image of FIGURE 1

Structures of -, -, and -defensins. The backbone and disulfide structures are shown of RK-1 (upper left), a monomeric rabbit -defensin ( ); HNP-3 (upper right), a dimeric human -defensin; hBD-1 (lower left), a monomeric human -defensin; and RTD-1 (lower right), a -defensin from rhesus macaque.

Citation: Ouellette A, Selsted M. 2003. Antimicrobial Peptide Effectors of Small Intestinal Innate Immunity, p 191-221. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch12
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Image of FIGURE 2

Primary structures of Paneth cell -defensins. The single letter notation amino acid sequences of mouse cryptdins 1 to 6, human Paneth cell -defensins HD-5 and HD-6, and rat Paneth cell -defensin RD-5 were positioned manually to align conserved Cys, Glu, and Gly residues. Dash characters denote spaces introduced to maintain the alignment of conserved amino acids (bolded typeface) that are conserved in all known -defensin peptides. The cysteine connectivities that characterize the -defensin tridisulfide array are shown. The HD-5 and HD-6 peptides have been purified from ileal neobladder urine ( ), and the RD-5 peptide sequence was deduced from the cDNA sequence and by homology with mouse cryptdin N termini ( ).

Citation: Ouellette A, Selsted M. 2003. Antimicrobial Peptide Effectors of Small Intestinal Innate Immunity, p 191-221. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch12
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Image of FIGURE 3

Recognition and cleavage of mouse procryptdins by MMP-7. In A, samples of procryptdins A, B, and C were incubated overnight with (+) or without (–) MMP-7, and samples of those digests were resolved electrophoretically and stained. Electrophoretic mobilities of individual components are noted at left in descending order as follows: MMP-7, matrilysin; PC, purified procryptdins; Crp, MMP-7-activated cryptdin peptides. As described in the text, MMP-7 is the activating metalloproteinase for all mouse Paneth cell -defensins. Dashes at right denote, in descending order, the position of 28-, 18-, 15.6-, and 7.6-kDa molecular size markers. In B, the consensus cleavage sites disclosed by protein sequencing of MMP-7 digests of procryptdins A to C are noted by asterisks () that interrupt the procryptdin-1 sequence, and the pound character (#) shows the N terminus of procryptdin intermediates purified from mouse small bowel by Putsep et al. ( ) that were not evident in the procryptdin A to C digests. Numerals above the primary structure refer to residue positions, with the initiating Met residue in preprocryptdin-1 as residue #1. Reprinted from reference with permission.

Citation: Ouellette A, Selsted M. 2003. Antimicrobial Peptide Effectors of Small Intestinal Innate Immunity, p 191-221. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch12
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Image of FIGURE 4

Release of microbicidal peptide activity by crypt Paneth cells in response to live bacteria. Crypts (solid circles) or villi (shaded diamonds) were isolated from adult mice and incubated in numbers shown with 103 of serovar Typhimurium CFU for 1 h at 37°C in 50 l of isotonic buffer. Viable CFU were quantitated by plating the entire mixtures on semisolid nutrient media overnight. Data points show surviving bacteria from individual replicate mixtures. Open circles represent surviving bacteria after incubation of 10 CFU for 1 h at 37°C in 50 l of isotonic buffer in the absence of crypts or villi. As noted in the text, bacteria exposed to crypts die in response to Paneth cell secretions ( ), but equivalent exposure to villus epithelium does not affect serovar Typhimurium viability. Reprinted from reference 11 with permission.

Citation: Ouellette A, Selsted M. 2003. Antimicrobial Peptide Effectors of Small Intestinal Innate Immunity, p 191-221. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch12
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Image of FIGURE 5

Role of mIKCa1 in Paneth cell secretion. Exposure of Paneth cells to pharmacologic agents ( ) or bacterial antigens results in an initial increase in cytosolic Ca ([Cai]) by mobilization of intracellular stores. mIKCa1 channels in the Paneth cell membrane would be predicted to open as cytosolic [Cai] approaches 300 nM, providing the counterbalancing K_ efflux necessary to sustain Ca entry from the external milieu ( ). As noted in detail in the text, blockade of mIKCa1 would depolarize the membrane and attenuate the calcium-signaling response required to generate a complete Paneth cell secretory response. Electron micrograph was generously provided by Susan J. Hagen, Beth Israel Deaconess Medical Center, Boston, Mass.

Citation: Ouellette A, Selsted M. 2003. Antimicrobial Peptide Effectors of Small Intestinal Innate Immunity, p 191-221. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch12
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Image of FIGURE 6

Dense granules in mouse small intestinal intermediate granulomucous cells during infection. (A) This transmission electron micrograph shows evidence of extensive Paneth cell degranulation into the crypt lumen (L). Cells at the top of the field display large electron dense granules within electron-lucent mucus-containing granules, the hallmark of intermediate granulomucous cells. (B) Two representative intermediate cells that were detected above the crypt villus junction. Such cells are immunopositive for mouse Paneth cell -defensins and are not found after clearance of the infection ( ). Reprinted from reference , with permission.

Citation: Ouellette A, Selsted M. 2003. Antimicrobial Peptide Effectors of Small Intestinal Innate Immunity, p 191-221. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch12
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Image of FIGURE 7

Paneth cells in the context of the small intestinal villus-crypt axis ( ). Stem cells in small intestinal crypts divide, and their progeny migrate upward toward the villi or descend toward the base of the crypt. Migration toward the villus tips is accompanied by cellular differentiation into absorptive enterocytes, goblet cells, or enteroendocrine cells. The life span of these villus cells from their origin in the crypt, through migration and differentiation, until apoptotic death and exfoliation into the lumen is approximately 2 to 5 days. Stem cell progeny that migrate to the crypt base differentiate into Paneth cells that live for several weeks. (Inset) Paneth cells release secretory vesicles into the narrow lumen of the crypt ( ). The secretory responses are mediated by Ca2+, and the secretions contain -defensins, lysozyme, and secretory phospholipase A2. Illustration by D. Schumick, Department of Medical Illustration, Cleveland Clinic Foundation, ©2000, Cleveland Clinic Foundation. Reprinted from reference , with permission.

Citation: Ouellette A, Selsted M. 2003. Antimicrobial Peptide Effectors of Small Intestinal Innate Immunity, p 191-221. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch12
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1. Agerberth, B.,, H. Gunne,, J. Odeberg,, P. Kogner,, H. G. Boman,, and G. H. Gudmundsson. 1995. FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis. Proc. Natl. Acad. Sci. USA 92:195199.
2. Agerberth, B.,, J. Y. Lee,, T. Bergman,, M. Carlquist,, H. G. Boman,, V. Mutt,, and H. Jornvall. 1991. Amino acid sequence of PR-39. Isolation from pig intestine of a new member of the family of proline-arginine-rich antibacterial peptides. Eur. J. Biochem. 202:849854.
3. Aho, H. J.,, B. Sternby,, M. Kallajoki,, and T. J. Nevalainen. 1989. Carboxyl ester lipase in human tissues and in acute pancreatitis. Int. J. Pancreatol. 5:123134.
4. Akira, S.,, K. Takeda,, and T. Kaisho. 2001. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat. Immunol. 2:675680.
5. Albedi, F. M.,, E. Lorenzetti,, M. Contini,, and F. Nardi. 1984. Immature Paneth cells in intestinal metaplasia of gastric mucosa. Appl. Pathol. 2:4348.
6. Aley, S. B.,, M. Zimmerman,, M. Hetsko,, M. E. Selsted,, and F. D. Gillin. 1994. Killing of Giardia lamblia by cryptdins and cationic neutrophil peptides. Infect. Immun. 62:53975403.
7. Alnadjim, Z.,, S. M. Cohn,, T. Ayabe,, S. Biafora,, A. J. Ouellette,, and T. A. Barrett. 2001. T cell activation instructs epithelial lineage development by inducing Paneth cell expansion and cryptdin production in intestinal crypts. Gastroenterology 120:A21 (Abstract).
8. Alper, S. L.,, H. Rossmann,, S. Wilhelm,, A. K. Stuart-Tilley,, B. E. Shmukler,, and U. Seidler. 1999. Expression of AE2 anion exchanger in mouse intestine. Am. J. Physiol. 277:G321G332.
9. Ariza, A.,, D. Lopez,, E. M. Castella,, C. Munoz,, M. J. Zujar,, and J. L. Mate. 1996. Ex pression of CD15 in normal and metaplastic Paneth cells of the digestive tract. J. Clin. Pathol. 49:474477.
10. Ayabe, T.,, D. P. Satchell,, P. Pesendorfer,, H. Tanabe,, C. L. Wilson,, S. J. Hagen,, and A. J. Ouellette. 2002. Activation of Paneth cell alpha-defensins in mouse small intestine. J. Biol. Chem. 277:52195228.
11. Ayabe, T.,, D. P. Satchell,, C. L. Wilson,, W. C. Parks,, M. E. Selsted,, and A. J. Ouellette. 2000. Secretion of microbicidal alphadefensins by intestinal Paneth cells in response to bacteria. Nat. Immunol. 1:113118.
12. Ayabe, T.,, H. Wulff,, D. Darmoul,, M. D. Cahalan,, K. G. Chandy,, and A. J. Ouellette. 2002. Modulation of mouse Paneth cell alphadefensin secretion by mIKCa1, a Ca2+-activated, intermediate conductance potassium channel. J. Biol. Chem. 277:37933800.
13. Ballance, W. A.,, B. B. Dahms,, N. Shenker,, and R. M. Kliegman. 1990. Pathology of neonatal necrotizing enterocolitis: a ten-year experience. J. Pediatr. 117:S6S13.
14. Bals, R.,, X. Wang,, R. L. Meegalla,, S. Wattler,, D. J. Weiner,, M. C. Nehls,, and J. M. Wilson. 1999. Mouse beta-defensin 3 is an inducible antimicrobial peptide expressed in the epithelia of multiple organs. Infect. Immun. 67: 35423547.
15. Bals, R.,, X. Wang,, Z. Wu,, T. Freeman,, V. Bafna,, M. Zasloff,, and J. M. Wilson. 1998. Human beta-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung. J. Clin. Invest. 102:874880.
16. Bals, R.,, X. Wang,, M. Zasloff,, and J. M. Wilson. 1998. The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface. Proc. Natl. Acad. Sci. USA 95: 95419546.
17. Bateman, A.,, R. J. MacLeod,, P. Lembessis,, J. Hu,, F. Esch,, and S. Solomon. 1996. The isolation and characterization of a novel corticostatin/defensin-like peptide from the kidney. J. Biol. Chem. 271:1065410659.
18. Bevins, C. L.,, D. E. Jones,, A. Dutra,, J. Schaffzin,, and M. Muenke. 1996. Human enteric defensin genes: chromosomal map position and a model for possible evolutionary relationships. Genomics 31:95106.
19. Bevins, C. L.,, E. Martin-Porter,, and T. Ganz. 1999. Defensins and innate host defence of the gastrointestinal tract. Gut 45:911915.
20. Bjerknes, M.,, and H. Cheng. 1981. The stemcell zone of the small intestinal epithelium. I. Evidence from Paneth cells in the adult mouse. Am. J. Anat. 160:5163.
21. Bohe, M.,, A. Borgstrom,, C. Lindstrom,, and K. Ohlsson. 1984. Trypsin-like immunoreactivity in human Paneth cells. Digestion 30:271275.
22. Bohe, M.,, C. Lindstrom,, and K. Ohlsson. 1986. Immunohistochemical demonstration of pancreatic secretory proteins in human paneth cells. Scand. J. Gastroenterol. Suppl. 126:6568.
23. Boman, H. G. 1991. Antibacterial peptides: key components needed in immunity. Cell 65:205207.
24. Boman, H. G. 1995. Peptide antibiotics and their role in innate immunity. Annu. Rev. Immunol. 13:6192.
25. Brown, E. G.,, and A. Y. Sweet. 1982. Neonatal necrotizing enterocolitis. Pediatr. Clin. North Am. 29:11491170.
26. Bry, L.,, P. Falk,, K. Huttner,, A. Ouellette,, T. Midtvedt,, and J. I. Gordon. 1994. Paneth cell differentiation in the developing intestine of normal and transgenic mice. Proc. Natl. Acad. Sci. USA 91:1033510339.
27. Bry, L.,, P. G. Falk,, T. Midtvedt,, and J. I. Gordon. 1996. A model of host-microbial interactions in an open mammalian ecosystem. Science 273:13801383.
28. Cahalan, M. D.,, and K. G. Chandy. 1997. Ion channels in the immune system as targets for immunosuppression. Curr. Opin. Biotechnol. 8: 749756.
29. Calvert, R.,, G. Bordeleau,, G. Grondin,, A. Vezina,, and J. Ferrari. 1988. On the presence of intermediate cells in the small intestine. Anat. Rec. 220:291295.
30. Casteels, P.,, C. Ampe,, F. Jacobs,, and P. Tempst. 1993. Functional and chemical characterization of Hymenoptaecin, an antibacterial polypeptide that is infection-inducible in the honeybee (Apis mellifera). J. Biol. Chem. 268: 70447054.
31. Cheng, H. 1974. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. IV. Paneth cells. Am. J. Anat. 141:521535.
32. Christa, L.,, F. Carnot,, M. T. Simon,, F. Levavasseur,, M. G. Stinnakre,, C. Lasserre,, D. Thepot,, B. Clement,, E. Devinoy,, and C. Brechot. 1996. HIP/PAP is an adhesive protein expressed in hepatocarcinoma, normal Paneth, and pancreatic cells. Am. J. Physiol. 271:G993G1002.
33. Clark, D. P.,, S. Durell,, W. L. Maloy,, and M. Zasloff. 1994. Ranalexin. A novel antimicrobial peptide from bullfrog (Rana catesbeiana) skin, structurally related to the bacterial antibiotic, polymyxin. J. Biol. Chem. 269:1084910855.
34. Condon, M. R.,, A. Viera,, M. D’Alessio,, and G. Diamond. 1999. Induction of a rat enteric defensin gene by hemorrhagic shock. Infect. Immun. 67:47874793.
35. Cunliffe, R. N.,, F. R. Rose,, J. Keyte,, L. Abberley,, W. C. Chan,, and Y. R. Mahida. 2001. Human defensin 5 is stored in precursor form in normal Paneth cells and is expressed by some villous epithelial cells and by metaplastic Paneth cells in the colon in inflammatory bowel disease. Gut 48:176185.
36. Cunningham-Rundles, C. 2001. Physiology of IgA and IgA deficiency. J. Clin. Immunol. 21: 303309.
37. Cuthbert, A. P.,, S. A. Fisher,, M. M. Mirza,, K. King,, J. Hampe,, P. J. Croucher,, S. Mascheretti,, J. Sanderson,, A. Forbes,, J. Mansfield,, S. Schreiber,, C. M. Lewis,, and C. G. Mathew. 2002. The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology 122: 867874.
38. Darmoul, D.,, D. Brown,, M. E. Selsted,, and A. J. Ouellette. 1997. Cryptdin gene expression in developing mouse small intestine. Am. J. Physiol. 272:G197G206.
39. Darmoul, D.,, and A. J. Ouellette. 1996. Positional specificity of defensin gene expression reveals Paneth cell heterogeneity in mouse small intestine. Am. J. Physiol. 271:G68G74.
40. de Bruin, W. C.,, M. J. Wagenmans,, and W. H. Peters. 2000. Expression of glutathione S-transferase alpha, P1-1 and T1-1 in the human gastrointestinal tract. Jpn. J. Cancer Res. 91:310316.
41. Diamond, G.,, M. Zasloff,, H. Eck,, M. Brasseur,, W. L. Maloy,, and C. L. Bevins. 1991. Tracheal antimicrobial peptide, a cysteine-rich peptide from mammalian tracheal mucosa: peptide isolation and cloning of a cDNA. Proc. Natl. Acad. Sci. USA 88:39523956.
42. Dimopoulos, G.,, A. Richman,, H. M. Muller,, and F. C. Kafatos. 1997. Molecular immune responses of the mosquito Anopheles gambiae to bacteria and malaria parasites. Proc. Natl. Acad. Sci. USA 94:1150811513.
43. Dorschner, R. A.,, V. K. Pestonjamasp,, S. Tamakuwala,, T. Ohtake,, J. Rudisill,, V. Nizet,, B. Agerberth,, G. H. Gudmundsson,, and R. L. Gallo. 2001. Cutaneous injury induces the release of cathelicidin anti-microbial peptides active against group A Streptococcus. J. Invest. Dermatol. 117:9197.
44. Eisenhauer, P. B.,, S. S. Harwig,, and R. I. Lehrer. 1992. Cryptdins: antimicrobial defensins of the murine small intestine. Infect. Immun. 60: 35563565.
45. Erlandsen, S. L.,, C. B. Rodning,, C. Montero,, J. A. Parsons,, E. A. Lewis,, and I. D. Wilson. 1976. Immunocytochemical identification and localization of immunoglobulin A within Paneth cells of the rat small intestine. J. Histochem. Cytochem. 24:10851092.
46. Falk, P. G.,, L. V. Hooper,, T. Midtvedt,, and J. I. Gordon. 1998. Creating and maintaining the gastrointestinal ecosystem: what we know and need to know from gnotobiology. Microbiol. Mol. Biol. Rev. 62:11571170.
47. Fanger, C. M.,, S. Ghanshani,, N. J. Logsdon,, H. Rauer,, K. Kalman,, J. Zhou,, K. Beckingham,, K. G. Chandy,, M. D. Cahalan,, and J. Aiyar. 1999. Calmodulin mediates calciumdependent activation of the intermediate conductance KCa channel, IKCa1. J. Biol. Chem. 274: 57465754.
48. Fanger, C. M.,, H. Rauer,, A. L. Neben,, M. J. Miller,, H. Wulff,, J. C. Rosa,, C. R. Ganellin,, K. G. Chandy,, and M. D. Cahalan. 2001. Calcium-activated potassium channels sustain calcium signaling in T lymphocytes. Selective blockers and manipulated channel expression levels. J. Biol. Chem. 276:1224912256.
49. Fehlbaum, P.,, P. Bulet,, S. Chernysh,, J. P. Briand,, J. P. Roussel,, L. Letellier,, C. Hetru,, and J. A. Hoffmann. 1996. Structure-activity analysis of thanatin, a 21-residue inducible insect defense peptide with sequence homology to frog skin antimicrobial peptides. Proc. Natl. Acad. Sci. USA 93:12211225.
50. Fernandes, P. R.,, D. A. Samuelson,, W. R. Clark,, and R. J. Cousins. 1997. Immunohistochemical localization of cysteine-rich intestinal protein in rat small intestine. Am. J. Physiol. 272:G751G759.
51. Frydman, C. P.,, I. J. Bleiweiss,, P. D. Unger,, R. E. Gordon,, and N. V. Brazenas. 1992. Paneth cell-like metaplasia of the prostate gland. Arch. Pathol. Lab. Med. 116:274276.
52. Frye, M.,, J. Bargon,, N. Dauletbaev,, A. Weber,, T. O. Wagner,, and R. Gropp. 2000. Expression of human alpha-defensin 5 (HD5) mRNA in nasal and bronchial epithelial cells. J. Clin. Pathol. 53:770773.
53. Ganz, T. 1994. Biosynthesis of defensins and other antimicrobial peptides. CIBA Found. Symp. 186:6271; discussion, p. 71-76.
54. Ganz, T. 1999. Defensins and host defense. Science 286:420421.
55. Ganz, T. 2001. Defensins in the urinary tract and other tissues. J. Infect. Dis. 183(Suppl. 1): S41S42.
56. Ganz, T. 2000. Paneth cells—guardians of the gut cell hatchery. Nat. Immunol. 1:99100.
57. Ganz, T.,, and R. I. Lehrer. 1999. Antibiotic peptides from higher eukaryotes: biology and applications. Mol. Med. Today 5:292297.
58. Ganz, T.,, and R. I. Lehrer. 1998. Antimicrobial peptides of vertebrates. Curr. Opin. Immunol. 10:4144.
59. Ganz, T.,, L. Liu,, E. V. Valore,, and A. Oren. 1993. Posttranslational processing and targeting of transgenic human defensin in murine granulocyte, macrophage, fibroblast, and pituitary adenoma cell lines. Blood 82:641650.
60. Ganz, T.,, M. E. Selsted,, D. Szklarek,, S. S. Harwig,, K. Daher,, D. F. Bainton,, and R. I. Lehrer. 1985. Defensins. Natural peptide antibiotics of human neutrophils. J. Clin. Invest. 76: 14271435.
61. Gapin, L.,, H. Cheroutre,, and M. Kronenberg. 1999. Cutting edge: TCR alpha beta+ CD8 alpha alpha+ T cells are found in intestinal intraepithelial lymphocytes of mice that lack classical MHC class I molecules. J. Immunol. 163: 41004104.
62. Garabedian, E. M.,, L. J. Roberts,, M. S. McNevin,, and J. I. Gordon. 1997. Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice. J. Biol. Chem. 272:2372923740.
63. Geyer, G. 1973. Lysozyme in Paneth cell secretions. Acta Histochem. 45:126132.
64. Ghanshani, S.,, H. Wulff,, M. J. Miller,, H. Rohm,, A. Neben,, G. A. Gutman,, M. D. Cahalan,, and K. G. Chandy. 2000. Upregulation of the IKCa1 potassium channel during T-cell activation. Molecular mechanism and functional consequences. J. Biol. Chem. 275: 3713737149.
65. Ghoos, Y.,, and G. Vantrappen. 1971. The cytochemical localization of lysozyme in Paneth cell granules. Histochem. J. 3:175178.
66. Goldman, M. J.,, G. M. Anderson,, E. D. Stolzenberg,, U. P. Kari,, M. Zasloff,, and J. M. Wilson. 1997. Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell 88:553560.
67. Gordon, J. I.,, and M. L. Hermiston. 1994. Differentiation and self-renewal in the mouse gastrointestinal epithelium. Curr. Opin. Cell. Biol. 6:795803.
68. Gordon, J. I.,, L. V. Hooper,, M. S. Mc-Nevin,, M. Wong,, and L. Bry. 1997. Epithelial cell growth and differentiation. III. Promoting diversity in the intestine: conversations between the microflora, epithelium, and diffuse GALT. Am. J. Physiol 273:G565G570.
69. Grabsch, H.,, A. Pereverzev,, M. Weiergraber,, M. Schramm,, M. Henry,, R. Vajna,, R. E. Beattie,, S. G. Volsen,, U. Klockner,, J. Hescheler,, and T. Schneider. 1999. Immunohistochemical detection of alpha1E voltagegated Ca(2+) channel isoforms in cerebellum, INS-1 cells, and neuroendocrine cells of the digestive system. J. Histochem. Cytochem. 47:981994.
70. Grandjean, V.,, S. Vincent,, L. Martin,, M. Rassoulzadegan,, and F. Cuzin. 1997. Antimicrobial protection of the mouse testis: synthesis of defensins of the cryptdin family. Biol. Reprod. 57:11151122.
71. Groblewski, G. E.,, M. Yoshida,, H. Yao,, J. A. Williams,, and S. A. Ernst. 1999. Immunolocalization of CRHSP28 in exocrine digestive glands and gastrointestinal tissues of the rat. Am. J. Physiol. 276:G219G226.
72. Hampe, J.,, H. Frenzel,, M. M. Mirza,, P. J. Croucher,, A. Cuthbert,, S. Mascheretti,, K. Huse,, M. Platzer,, S. Bridger,, B. Meyer,, P. Nurnberg,, P. Stokkers,, M. Krawczak,, C. G. Mathew,, M. Curran,, and S. Schreiber. 2002. Evidence for a NOD2-independent susceptibility locus for inflammatory bowel disease on chromosome 16p. Proc. Natl. Acad. Sci. USA 99:321326.
73. Harder, J.,, J. Bartels,, E. Christophers,, and J. M. Schroder. 2001. Isolation and characterization of human beta-defensin-3, a novel human inducible peptide antibiotic. J. Biol. Chem. 276: 57075713.
74. Harder, J.,, J. Bartels,, E. Christophers,, and J. M. Schroder. 1997. A peptide antibiotic from human skin. Nature 387:861.
75. Hase, K.,, L. Eckmann,, J. D. Leopard,, N. Varki,, and M. F. Kagnoff. 2002. Cell differentiation is a key determinant of cathelicidin LL-37/human cationic antimicrobial protein 18 expression by human colon epithelium. Infect. Immun. 70:953963.
76. Herrmann, J. E.,, S. C. Chen,, D. H. Jones,, A. Tinsley-Bown,, E. F. Fynan,, H. B. Greenberg,, and G. H. Farrar. 1999. Immune responses and protection obtained by oral immunization with rotavirus VP4 and VP7 DNA vaccines encapsulated in microparticles. Virology 259:148153.
77. Hill, C. P.,, J. Yee,, M. E. Selsted,, and D. Eisenberg. 1991. Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization. Science 251:14811485.
78. Hoffmann, J. A.,, F. C. Kafatos,, C. A. Janeway,, and R. A. Ezekowitz. 1999. Phylogenetic perspectives in innate immunity. Science 284:13131318.
79. Hooper, L. V.,, L. Bry,, P. G. Falk,, and J. I. Gordon. 1998. Host-microbial symbiosis in the mammalian intestine: exploring an internal ecosystem. Bioessays 20:336343.
80. Hooper, L. V.,, and J. I. Gordon. 2001. Commensal host-bacterial relationships in the gut. Science 292:11151118.
81. Hooper, L. V.,, M. H. Wong,, A. Thelin,, L. Hansson,, P. G. Falk,, and J. I. Gordon. 2001. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291:881884.
82. Hoover, D. M.,, O. Chertov,, and J. Lubkowski. 2001. The structure of human betadefensin-1. New insights into structural properties of beta-defensins. J. Biol. Chem. 276: 3902139026.
83. Hoover, D. M.,, K. R. Rajashankar,, R. Blumenthal,, A. Puri,, J. J. Oppenheim,, O. Chertov,, and J. Lubkowski. 2000. The structure of human beta-defensin-2 shows evidence of higher order oligomerization. J. Biol. Chem. 275: 3291132918.
84. Horvath, K.,, J. C. Papadimitriou,, A. Rabsztyn,, C. Drachenberg,, and J. T. Tildon. 1999. Gastrointestinal abnormalities in children with autistic disorder. J. Pediatr. 135:559563.
85. Hristova, K.,, M. E. Selsted,, and S. H. White. 1997. Critical role of lipid composition in membrane permeabilization by rabbit neutrophil defensins. J. Biol. Chem. 272:2422424233.
86. Hristova, K.,, M. E. Selsted,, and S. H. White. 1996. Interactions of monomeric rabbit neutrophil defensins with bilayers: comparison with dimeric human defensin HNP-2. Biochemistry 35:1188811894.
87. Huang, H. W. 1999. Peptide-lipid interactions and mechanisms of antimicrobial peptides. Novartis Found. Symp. 225:188200; discussion, p. 200-206.
88. Hultmark, D.,, H. Steiner,, T. Rasmuson,, and H. G. Boman. 1980. Insect immunity. Purification and properties of three inducible bactericidal proteins from hemolymph of immunized pupae of Hyalophora cecropia. Eur. J. Biochem. 106:716.
89. Huttner, K. M.,, and C. L. Bevins. 1999. Antimicrobial peptides as mediators of epithelial host defense. Pediatr. Res. 45:785794.
90. Huttner, K. M.,, D. J. Brezinski-Caliguri,, M. M. Mahoney,, and G. Diamond. 1998. Antimicrobial peptide expression is developmentally regulated in the ovine gastrointestinal tract. J. Nutr. 128:297S299S.
91. Huttner, K. M.,, M. R. Lambeth,, H. R. Burkin,, D. J. Burkin,, and T. E. Broad. 1998. Localization and genomic organization of sheep antimicrobial peptide genes. Gene 206:8591.
92. Huttner, K. M.,, M. E. Selsted,, and A. J. Ouellette. 1994. Structure and diversity of the murine cryptdin gene family. Genomics 19:448453.
93. Iida, K. I.,, O. Miyaishi,, Y. Iwata,, K. I. Kozaki,, M. Matsuyama,, and S. Saga. 1996. Distinct distribution of protein disulfide isomerase family proteins in rat tissues. J. Histochem. Cytochem. 44:751759.
94. Imler, J. L.,, and J. A. Hoffmann. 2000. Toll and Toll-like proteins: an ancient family of receptors signaling infection. Rev. Immunogenet. 2:294304.
95. Jia, H. P.,, T. Starner,, M. Ackermann,, P. Kirby,, B. F. Tack,, and P. B. McCray, Jr. 2001. Abundant human beta-defensin-1 expression in milk and mammary gland epithelium. J. Pediatr. 138:109112.
96. Jia, H. P.,, S. A. Wowk,, B. C. Schutte,, S. K. Lee,, A. Vivado,, B. F. Tack,, C. L. Bevins,, and P. B. McCray, Jr. 2000. A novel murine beta-defensin expressed in tongue, esophagus, and trachea. J. Biol. Chem. 275: 3331433320.
97. Jones, D. E.,, and C. L. Bevins. 1993. Defensin-6 mRNA in human Paneth cells: implications for antimicrobial peptides in host defense of the human bowel. FEBS Lett. 315:187192.
98. Jones, D. E.,, and C. L. Bevins. 1992. Paneth cells of the human small intestine express an antimicrobial peptide gene. J. Biol. Chem. 267:2321623225.
989. Judge, T.,, and G. R. Lichtenstein. 2002. The NOD2 gene and Crohn’s disease: another triumph for molecular genetics. Gastroenterology 122:826828.
100. Kamal, M.,, D. Wakelin,, and Y. Mahida. 2001. Mucosal responses to infection with Trichinella spiralis in mice. Parasite 8:S110S113.
101. Kamal, M.,, D. Wakelin,, A. J. Ouellette,, A. Smith,, D. K. Podolsky,, and Y. R. Mahida. 2001. Mucosal T cells regulate Paneth and intermediate cell numbers in the small intestine of T. spiralis-infected mice. Clin. Exp. Immunol. 126:117125.
102. Keshav, S.,, L. Lawson,, L. P. Chung,, M. Stein,, V. H. Perry,, and S. Gordon. 1990. Tumor necrosis factor mRNA localized to Paneth cells of normal murine intestinal epithelium by in situ hybridization. J. Exp. Med. 171:327332.
103. Kindon, H.,, C. Pothoulakis,, L. Thim,, K. Lynch-Devaney,, and D. K. Podolsky. 1995. Trefoil peptide protection of intestinal epithelial barrier function: cooperative interaction with mucin glycoprotein. Gastroenterology 109:516523.
104. Kliegman, R. M. 1990. Models of the pathogenesis of necrotizing enterocolitis. J. Pediatr. 117:S2S5.
105. Kokryakov, V. N.,, S. S. Harwig,, E. A. Panyutich,, A. A. Shevchenko,, G. M. Aleshina,, O. V. Shamova,, H. A. Korneva,, and R. I. Lehrer. 1993. Protegrins: leukocyte antimicrobial peptides that combine features of corticostatic defensins and tachyplesins. FEBS Lett. 327:231236.
106. Kraehenbuhl, J. P.,, E. Pringault,, and M. R. Neutra. 1997. Review article: Intestinal epithelia and barrier functions. Aliment. Pharmacol. Ther. 11(Suppl. 3):38; discussion, p. 8-9.
107. Krisanaprakornkit, S.,, J. R. Kimball,, and B. A. Dale. 2002. Regulation of human betadefensin-2 in gingival epithelial cells: the involvement of mitogen-activated protein kinase pathways, but not the NF-kappaB transcription factor family. J. Immunol. 168:316324.
108. Krisanaprakornkit, S.,, A. Weinberg,, C. N. Perez,, and B. A. Dale. 1998. Expression of the peptide antibiotic human beta-defensin 1 in cultured gingival epithelial cells and gingival tissue. Infect. Immun. 66:42224228.
109. Kuzuhara, T.,, Y. Nakajima,, K. Matsuyama,, and S. Natori. 1990. Determination of the disulfide array in sapecin, an antibacterial peptide of Sarcophaga peregrina (flesh fly). J. Biochem. (Tokyo) 107:514518.
110. Kwon, M. Y.,, S. Y. Hong,, and K. H. Lee. 1998. Structure-activity analysis of brevinin 1E amide, an antimicrobial peptide from Rana esculenta. Biochim. Biophys. Acta 1387:239248.
111. Landon, C.,, P. Sodano,, C. Hetru,, J. Hoffmann,, and M. Ptak. 1997. Solution structure of drosomycin, the first inducible antifungal protein from insects. Protein Sci. 6:18781884.
112. Lasserre, C.,, C. Colnot,, C. Brechot,, and F. Poirier. 1999. HIP/PAP gene, encoding a Ctype lectin overexpressed in primary liver cancer, is expressed in nervous system as well as in intestine and pancreas of the postimplantation mouse embryo. Am. J. Pathol. 154:16011610.
113. Lee, S. H.,, M. S. Shin,, W. S. Park,, S. Y. Kim,, S. M. Dong,, H. K. Lee,, J. Y. Park,, R. R. Oh,, J. J. Jang,, J. Y. Lee,, and N. J. Yoo. 1999. Immunohistochemical analysis of Fas ligand expression in normal human tissues. APMIS 107:10131019.
114. Lehane, M. J.,, D. Wu,, and S. M. Lehane. 1997. Midgut-specific immune molecules are produced by the blood-sucking insect Stomoxys calcitrans. Proc. Natl. Acad. Sci. USA 94:1150211507.
115. Lehrer, R. I.,, A. Barton,, K. A. Daher,, S. S. Harwig,, T. Ganz,, and M. E. Selsted. 1989. Interaction of human defensins with Escherichia coli. Mechanism of bactericidal activity. J. Clin. Invest. 84:553561.
116. Lehrer, R. I.,, and T. Ganz. 1999. Antimicrobial peptides in mammalian and insect host defence. Curr. Opin. Immunol. 11:2327.
117. Lehrer, R. I.,, and T. Ganz. 2002. Cathelicidins: a family of endogenous antimicrobial peptides. Curr. Opin. Hematol. 9:1822.
118. Lehrer, R. I.,, and T. Ganz. 2002. Defensins of vertebrate animals. Curr. Opin. Immunol. 14:96102.
119. Lehrer, R. I.,, T. Ganz,, and M. E. Selsted. 1988. Oxygen-independent bactericidal systems. Mechanisms and disorders. Hematol. Oncol. Clin. North Am. 2:159169.
120. Lehrer, R. I.,, M. E. Selsted,, D. Szklarek,, and J. Fleischmann. 1983. Antibacterial activity of microbicidal cationic proteins 1 and 2, natural peptide antibiotics of rabbit lung macrophages. Infect. Immun. 42:1014.
121. Lencer, W. I.,, G. Cheung,, G. R. Strohmeier,, M. G. Currie,, A. J. Ouellette,, M. E. Selsted,, and J. L. Madara. 1997. Induction of epithelial chloride secretion by channel-forming cryptdins 2 and 3. Proc. Natl. Acad. Sci. USA 94:85858589.
122. Leonova, L.,, V. N. Kokryakov,, G. Aleshina,, T. Hong,, T. Nguyen,, C. Zhao,, A. J. Waring,, and R. I. Lehrer. 2001. Circular minidefensins and posttranslational generation of molecular diversity. J. Leukoc. Biol. 70:461464.
123. Lesage, S.,, H. Zouali,, J. P. Cezard,, J. F. Colombel,, J. Belaiche,, S. Almer,, C. Tysk,, C. O’Morain,, M. Gassull,, V. Binder,, Y. Finkel,, R. Modigliani,, C. Gower-Rousseau,, J. Macry,, F. Merlin,, M. Chamaillard,, A. S. Jannot,, G. Thomas,, and J. P. Hugot. 2002. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am. J. Hum. Genet. 70:845857.
124. Linzmeier, R.,, D. Michaelson,, L. Liu,, and T. Ganz. 1993. The structure of neutrophil defensin genes. FEBS Lett. 321:267273.
125. Lopez-Boado, Y. S.,, C. L. Wilson,, L. V. Hooper,, J. I. Gordon,, S. J. Hultgren,, and W. C. Parks. 2000. Bacterial exposure induces and activates matrilysin in mucosal epithelial cells. J. Cell. Biol. 148:13051315.
126. Macpherson, A. J.,, D. Gatto,, E. Sainsbury,, G. R. Harriman,, H. Hengartner,, and R. M. Zinkernagel. 2000. A primitive T cellindependent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288:22222226.
127. Mallow, E. B.,, A. Harris,, N. Salzman,, J. P. Russell,, R. J. DeBerardinis,, E. Ruchelli,, and C. L. Bevins. 1996. Human enteric defensins. Gene structure and developmental expression. J. Biol. Chem. 271:40384045.
128. Mambula, S. S.,, E. R. Simons,, R. Hastey,, M. E. Selsted,, and S. M. Levitz. 2000. Human neutrophil-mediated nonoxidative antifungal activity against Cryptococcus neoformans. Infect. Immun. 68:62576264.
129. Mandard, N.,, D. Sy,, C. Maufrais,, J. M. Bonmatin,, P. Bulet,, C. Hetru,, and F. Vovelle. 1999. Androctonin, a novel antimicrobial peptide from scorpion Androctonus australis: solution structure and molecular dynamics simulations in the presence of a lipid monolayer. J. Biomol. Struct. Dyn. 17:367380.
130. Mantle, M.,, G. G. Forstner,, and J. F. Forstner. 1984. Antigenic and structural features of goblet-cell mucin of human small intestine. Biochem. J. 217:159167.
131. Masciotra, L.,, P. Lechene de la Porte,, J. M. Frigerio,, N. J. Dusetti,, J. C. Dagorn,, and J. L. Iovanna. 1995. Immunocytochemical localization of pancreatitis-associated protein in human small intestine. Dig. Dis. Sci. 40:519524.
132. Mashimo, H.,, D. K. Podolsky,, and M. C. Fishman. 1995. Structure and expression of murine intestinal trefoil factor: high evolutionary conservation and postnatal expression. Biochem. Biophys. Res. Commun. 210:3137.
133. Mashimo, H.,, D. C. Wu,, D. K. Podolsky,, and M. C. Fishman. 1996. Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science 274:262265.
134. Mathews, M.,, H. P. Jia,, J. M. Guthmiller,, G. Losh,, S. Graham,, G. K. Johnson,, B. F. Tack,, and P. B. McCray, Jr. 1999. Production of beta-defensin antimicrobial peptides by the oral mucosa and salivary glands. Infect. Immun. 67:27402745.
135. Matsubara, F. 1977. Morphological study of the Paneth cell. Paneth cells in intestinal metaplasia of the stomach and duodenum of man. Acta Pathol. Jpn. 27:677695.
136. Matsuyama, K.,, and S. Natori. 1988. Molecular cloning of cDNA for sapecin and unique expression of the sapecin gene during the development of Sarcophaga peregrina. J. Biol. Chem. 263:1711717121.
137. Matsuzaki, K.,, Y. Mitani,, K. Y. Akada,, O. Murase,, S. Yoneyama,, M. Zasloff,, and K. Miyajima. 1998. Mechanism of synergism between antimicrobial peptides magainin 2 and PGLa. Biochemistry 37:1514415153.
138. McNamara, N. A.,, R. Van,, O. S. Tuchin,, and S. M. Fleiszig. 1999. Ocular surface epithelia express mRNA for human beta defensin-2. Exp. Eye Res. 69:483490.
139. Merlin, D.,, G. Yue,, W. I. Lencer,, M. E. Selsted,, and J. L. Madara. 2001. Cryptdin-3 induces novel apical conductance(s) in Clsecretory, including cystic fibrosis, epithelia. Am. J. Physiol. Cell Physiol. 280:C296C302.
140. Michaelson, D.,, J. Rayner,, M. Couto,, and T. Ganz. 1992. Cationic defensins arise from charge-neutralized propeptides: a mechanism for avoiding leukocyte autocytotoxicity? J. Leukoc.Biol. 51:634639.
141. Michetti, P.,, N. Porta,, M. J. Mahan,, J. M. Slauch,, J. J. Mekalanos,, A. L. Blum,, J. P. Kraehenbuhl,, and M. R. Neutra. 1994. Monoclonal immunoglobulin A prevents adherence and invasion of polarized epithelial cell monolayers by Salmonella typhimurium. Gastroenterology 107:915923.
142. Moller, P.,, H. Walczak,, S. Reidl,, J. Strater,, and P. H. Krammer. 1996. Paneth cells express high levels of CD95 ligand transcripts: a unique property among gastrointestinal epithelia. Am. J. Pathol. 149:913.
143. Molmenti, E. P.,, D. H. Perlmutter,, and D. C. Rubin. 1993. Cell-specific expression of alpha 1-antitrypsin in human intestinal epithelium. J. Clin. Invest. 92:20222034.
144. Mor, A.,, V. H. Nguyen,, A. Delfour,, D. Migliore-Samour,, and P. Nicolas. 1991. Isolation, amino acid sequence, and synthesis of dermaseptin, a novel antimicrobial peptide of amphibian skin. Biochemistry 30:88248830.
145. Morita, Y.,, M. Sawada,, H. Seno,, S. Takaishi,, H. Fukuzawa,, N. Miyake,, H. Hiai,, and T. Chiba. 2001. Identification of xanthine dehydrogenase/xanthine oxidase as a rat Paneth cell zinc-binding protein. Biochim. Biophys. Acta 1540:4349.
146. Morrissey, S. M.,, and M. C. Tymvios. 1978. Acid mucins in human intestinal goblet cells. J. Pathol. 126:197208.
147. Mullins, J. E.,, and I. C. Fuentealba. 1998. Immunohistochemical detection of metallothionein in liver, duodenum and kidney after dietary copper-overload in rats. Histol. Histopathol. 13:627633.
148. Nakamura, T.,, H. Furunaka,, T. Miyata,, F. Tokunaga,, T. Muta,, S. Iwanaga,, M. Niwa,, T. Takao,, and Y. Shimonishi. 1988. Tachyplesin, a class of antimicrobial peptide from the hemocytes of the horseshoe crab (Tachypleus tridentatus). Isolation and chemical structure. J. Biol. Chem. 263:1670916713.
149. Nevalainen, T. J.,, J. M. Gronroos,, and M. Kallajoki. 1995. Expression of group II phospholipase A2 in the human gastrointestinal tract. Lab. Invest. 72:201208.
150. Newman, S. L.,, L. Gootee,, J. E. Gabay,, and M. E. Selsted. 2000. Identification of constituents of human neutrophil azurophil granules that mediate fungistasis against Histoplasma capsulatum. Infect. Immun. 68:56685672.
151. Nicolas, E.,, A. J. Nappi,, and B. Lemaitre. 1996. Expression of antimicrobial peptide genes after infection by parasitoid wasps in Drosophila. Dev. Comp. Immunol. 20:175181.
152. Nishimura, H.,, N. Nishimura,, and C. Tohyama. 1989. Immunohistochemical localization of metallothionein in developing rat tissues. J. Histochem. Cytochem. 37:715722.
153. Nizet, V.,, T. Ohtake,, X. Lauth,, J. Trowbridge,, J. Rudisill,, R. A. Dorschner,, V. Pestonjamasp,, J. Piraino,, K. Huttner,, and R. L. Gallo. 2001. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 414:454457.
154. Nyman, K. M.,, P. Ojala,, V. J. Laine,, and T. J. Nevalainen. 2000. Distribution of group II phospholipase A2 protein and mRNA in rat tissues. J. Histochem. Cytochem. 48:14691478.
155. Ogura, Y.,, D. K. Bonen,, N. Inohara,, D. L. Nicolae,, F. F. Chen,, R. Ramos,, H. Britton,, T. Moran,, R. Karaliuskas,, R. H. Duerr,, J. P. Achkar,, S. R. Brant,, T. M. Bayless,, B. S. Kirschner,, S. B. Hanauer,, G. Nunez,, and J. H. Cho. 2001. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603606.
156. Ohnishi, H.,, S. A. Ernst,, N. Wys,, M. McNiven,, and J. A. Williams. 1996. Rab3D localizes to zymogen granules in rat pancreatic acini and other exocrine glands. Am. J. Physiol. 271:G531G538.
157. O’Neil, D. A.,, S. P. Cole,, E. Martin-Porter,, M. P. Housley,, L. Liu,, T. Ganz,, and M. F. Kagnoff. 2000. Regulation of human beta-defensins by gastric epithelial cells in response to infection with Helicobacter pylori or stimulation with interleukin-1. Infect. Immun. 68:54125415.
158. O’Neil, D. A.,, E. M. Porter,, D. Elewaut,, G. M. Anderson,, L. Eckmann,, T. Ganz,, and M. F. Kagnoff. 1999. Expression and regulation of the human beta-defensins hBD-1 and hBD-2 in intestinal epithelium. J. Immunol. 163: 67186724.
159. Oppenheim, F. G.,, T. Xu,, F. M. Mc-Millian,, S. M. Levitz,, R. D. Diamond,, G. D. Offner,, and R. F. Troxler. 1988. Histatins, a novel family of histidine-rich proteins in human parotid secretion. Isolation, characterization, primary structure, and fungistatic effects on Candida albicans. J. Biol. Chem. 263:74727477.
160. Otvos, L., Jr. 2000. Antibacterial peptides isolated from insects. J. Pept. Sci. 6:497511.
161. Ouellette, A. J.,, and C. L. Bevins. 2001. Paneth cell defensins and innate immunity of the small bowel. Inflamm. Bowel Dis. 7:4350.
162. Ouellette, A. J.,, D. Darmoul,, D. Tran,, K. M. Huttner,, J. Yuan,, and M. E. Selsted. 1999. Peptide localization and gene structure of cryptdin 4, a differentially expressed mouse Paneth cell alpha-defensin. Infect. Immun. 67: 66436651.
163. Ouellette, A. J.,, M. M. Hsieh,, M. T. Nosek,, D. F. Cano-Gauci,, K. M. Huttner,, R. N. Buick,, and M. E. Selsted. 1994. Mouse Paneth cell defensins: primary structures and antibacterial activities of numerous cryptdin isoforms. Infect. Immun. 62:50405047.
164. Ouellette, A. J.,, D. Pravtcheva,, F. H. Ruddle,, and M. James. 1989. Localization of the cryptdin locus on mouse chromosome 8. Genomics 5:233239.
165. Ouellette, A. J.,, D. P. Satchell,, M. M. Hsieh,, S. J. Hagen,, and M. E. Selsted. 2000. Characterization of luminal Paneth cell alphadefensins in mouse small intestine. Attenuated antimicrobial activities of peptides with truncated amino termini. J. Biol. Chem. 275:3396933973.
166. Ouellette, A. J.,, and M. E. Selsted. 1996. Paneth cell defensins: endogenous peptide components of intestinal host defense. FASEB J. 10:12801289.
167. Panyutich, A. V.,, N. N. Voitenok,, R. I. Lehrer,, and T. Ganz. 1991. An enzyme immunoassay for human defensins. J. Immunol. Methods 141:149155.
168. Pardi, A.,, D. R. Hare,, M. E. Selsted,, R. D. Morrison,, D. A. Bassolino,, and A. C. Bach 2nd. 1988. Solution structures of the rabbit neutrophil defensin NP-5. J. Mol. Biol. 201:625636.
169. Pardi, A.,, X. L. Zhang,, M. E. Selsted,, J. J. Skalicky,, and P. F. Yip. 1992. NMR studies of defensin antimicrobial peptides. 2. Threedimensional structures of rabbit NP-2 and human HNP-1. Biochemistry 31:1135711364.
170. Park, C. H.,, E. V. Valore,, A. J. Waring,, and T. Ganz. 2001. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J. Biol. Chem. 276:78067810.
171. Parsons, S. M.,, and C. E. Smith. 1984. Ultrastructural localization of nicotinamide adenine dinucleotide phosphatase (NADPase) activity within columnar, goblet, and Paneth cells of rat small intestine. J. Histochem. Cytochem. 32:989997.
172. Peeters, T.,, and G. Vantrappen. 1975. The Paneth cell: a source of intestinal lysozyme. Gut 16:553558.
173. Peng, K. C.,, F. Cluzeaud,, M. Bens,, J. P. Van Huyen,, M. A. Wioland,, R. Lacave,, and A. Vandewalle. 1999. Tissue and cell distribution of the multidrug resistance-associated protein (MRP) in mouse intestine and kidney. J. Histochem. Cytochem. 47:757768.
174. Porter, E. M.,, C. L. Bevins,, D. Ghosh,, and T. Ganz. 2002. The multifaceted Paneth cell. Cell Mol. Life Sci. 59:156170.
175. Porter, E. M.,, L. Liu,, A. Oren,, P. A. Anton,, and T. Ganz. 1997. Localization of human intestinal defensin 5 in Paneth cell granules. Infect. Immun. 65:23892395.
176. Porter, E. M.,, M. A. Poles,, J. S. Lee,, J. Naitoh,, C. L. Bevins,, and T. Ganz. 1998. Isolation of human intestinal defensins from ileal neobladder urine. FEBS Lett. 434:272276.
177. Porter, E. M.,, E. van Dam,, E. V. Valore,, and T. Ganz. 1997. Broad-spectrum antimicrobial activity of human intestinal defensin 5. Infect. Immun. 65:23962401.
178. Poulsom, R.,, R. Chinery,, C. Sarraf,, E. N. Lalani,, G. Stamp,, G. Elia,, and N. Wright. 1992. Trefoil peptide expression in intestinal adaptation and renewal. Scand. J. Gastroenterol. 192(Suppl.):1728.
179. Putsep, K.,, L. G. Axelsson,, A. Boman,, T. Midtvedt,, S. Normark,, H. G. Boman,, and M. Andersson. 2000. Germ-free and colonized mice generate the same products from enteric prodefensins. J. Biol. Chem. 275:4047840482.
180. Qu, H.,, and A. M. Dvorak. 1997. Ultrastructural localization of osteopontin immunoreactivity in phagolysosomes and secretory granules of cells in human intestine. Histochem. J. 29:801812.
181. Quayle, A. J.,, E. M. Porter,, A. A. Nussbaum,, Y. M. Wang,, C. Brabec,, K. P. Yip,, and S. C. Mok. 1998. Gene expression, immunolocalization, and secretion of human defensin-5 in human female reproductive tract. Am. J. Pathol. 152:12471258.
182. Reilly, D. S.,, N. Tomassini,, C. L. Bevins,, and M. Zasloff. 1994. A Paneth cell analogue in Xenopus small intestine expresses antimicrobial peptide genes: conservation of an intestinal host-defense system. J. Histochem. Cytochem. 42:697704.
183. Rice, W. G.,, T. Ganz,, J. M. Kinkade, Jr.,, M. E. Selsted,, R. I. Lehrer,, and R. T. Parmley. 1987. Defensin-rich dense granules of human neutrophils. Blood 70:757765.
184. Rodning, C. B.,, I. D. Wilson,, and S. L. Erlandsen. 1976. Immunoglobulins within human small-intestinal Paneth cells. Lancet i:984987.
185. Rose, J.,, M. Franco,, and H. Greenberg. 1998. The immunology of rotavirus infection in the mouse. Adv. Virus. Res. 51:203235.
186. Rubin, D. C.,, K. A. Roth,, E. H. Birkenmeier,, and J. I. Gordon. 1991. Epithelial cell differentiation in normal and transgenic mouse intestinal isografts. J. Cell Biol. 113:11831192.
187. Rubin, D. C.,, E. Swietlicki,, K. A. Roth,, and J. I. Gordon. 1992. Use of fetal intestinal isografts from normal and transgenic mice to study the programming of positional information along the duodenal-to-colonic axis. J. Biol. Chem. 267:1512215133.
188. Rubio, C. A. 1989. Paneth cell adenoma of the stomach. Am. J. Surg. Pathol. 13:325328.
189. Rubio, C. A.,, L. Kanter,, J. Bjork,, B. Poppen,, and L. Bry. 1996. Paneth cell-rich flat adenoma of the rectum: report of a case. Jpn. J. Cancer Res. 87:109112.
190. Salzman, N. H.,, R. A. Polin,, M. C. Harris,, E. Ruchelli,, A. Hebra,, S. Zirin-Butler,, A. Jawad,, E. Martin Porter,, and C. L. Bevins. 1998. Enteric defensin expression in necrotizing enterocolitis. Pediatr. Res. 44:2026.
191. Sansonetti, A.,, H. Romeo,, P. Berthezene,, P. Scacchi,, N. Dusetti,, V. Keim,, J. C. Dagorn,, and J. L. Iovanna. 1995. Developmental, nutritional, and hormonal regulation of the pancreatitis-associated protein I and III gene expression in the rat small intestine. Scand. J. Gastroenterol. 30:664669.
192. Sartor, R. B. 1997. Pathogenesis and immune mechanisms of chronic inflammatory bowel diseases. Am. J. Gastroenterol. 92:5S11S.
193. Sartor, R. B. 1997. Review article: Role of the enteric microflora in the pathogenesis of intestinal inflammation and arthritis. Aliment. Pharmacol. Ther. 11(Suppl. 3):1722; discussion, p. 22-23.
194. Satoh, Y. 1988. Atropine inhibits the degranulation of Paneth cells in ex-germ-free mice. Cell Tissue Res. 253:397402.
195. Satoh, Y. 1988. Effect of live and heat-killed bacteria on the secretory activity of Paneth cells in germ-free mice. Cell Tissue Res. 251:8793.
196. Satoh, Y. 1984. Ultrastructure of Paneth cells in germ-free rats, with special reference to the secretory granules and lysosomes. Arch. Histol. Jpn. 47:293301.
197. Satoh, Y.,, Y. Habara,, K. Ono,, and T. Kanno. 1995. Carbamylcholine-and catecholamine-induced intracellular calcium dynamics of epithelial cells in mouse ileal crypts. Gastroenterology 108:13451356.
198. Satoh, Y.,, K. Ishikawa,, K. Ono,, and L. Vollrath. 1986. Quantitative light microscopic observations on Paneth cells of germ-free and ex-germ-free Wistar rats. Digestion 34:115121.
199. Satoh, Y.,, K. Ishikawa,, H. Tanaka,, Y. Oomori,, and K. Ono. 1988. Immunohistochemical observations of lysozyme in the Paneth cells of specific pathogen-free and germ-free mice. Acta Histochem. 83:185188.
200. Satoh, Y.,, M. R. Williams,, and Y. Habara. 1999. Effects of AIF4 and ATP on intracellular calcium dynamics of crypt epithelial cells in mouse small intestine. Cell Tissue Res. 298:295305.
201. Savidge, T. C.,, A. L. Morey,, D. J. Ferguson,, K. A. Fleming,, A. N. Shmakov,, and A. D. Phillips. 1995. Human intestinal development in a severe-combined immunodeficient xenograft model. Differentiation 58:361371.
202. Sawai, M. V.,, H. P. Jia,, L. Liu,, V. Aseyev,, J. M. Wiencek,, P. B. McCray, Jr.,, T. Ganz,, W. R. Kearney,, and B. F. Tack. 2001. The NMR structure of human beta-defensin-2 reveals a novel alpha-helical segment. Biochemistry 40:38103816.
203. Schmauder-Chock, E. A.,, and S. P. Chock. 1992. Prostaglandin E2 localization in the rat ileum. Histochem. J. 24:663672.
204. Schmauder-Chock, E. A.,, S. P. Chock,, and M. L. Patchen. 1994. Ultrastructural localization of tumour necrosis factor-alpha. Histochem J. 26:142151.
205. Schonwetter, B. S.,, E. D. Stolzenberg,, and M. A. Zasloff. 1995. Epithelial antibiotics induced at sites of inflammation. Science 267: 16451648.
206. Schutte, B. C.,, and P. B. McCray, Jr. 2002. β-Defensins in lung host defense. Annu. Rev. Physiol. 64:709748.
207. Selsted, M. E.,, D. M. Brown,, R. J. De-Lange,, and R. I. Lehrer. 1983. Primary structures of MCP-1 and MCP-2, natural peptide antibiotics of rabbit lung macrophages. J. Biol. Chem. 258:1448514489.
208. Selsted, M. E.,, and S. S. Harwig. 1989. Determination of the disulfide array in the human defensin HNP-2. A covalently cyclized peptide. J. Biol. Chem. 264:40034007.
209. Selsted, M. E.,, S. S. Harwig,, T. Ganz,, J. W. Schilling,, and R. I. Lehrer. 1985. Primary structures of three human neutrophil defensins. J. Clin. Invest. 76:14361439.
210. Selsted, M. E.,, S. I. Miller,, A. H. Henschen,, and A. J. Ouellette. 1992. Enteric defensins: antibiotic peptide components of intestinal host defense. J. Cell Biol. 118:929936.
211. Selsted, M. E.,, M. J. Novotny,, W. L. Morris,, Y. Q. Tang,, W. Smith,, and J. S. Cullor. 1992. Indolicidin, a novel bactericidal tridecapeptide amide from neutrophils. J. Biol. Chem. 267:42924295.
212. Selsted, M. E.,, Y. Q. Tang,, W. L. Morris,, P. A. McGuire,, M. J. Novotny,, W. Smith,, A. H. Henschen,, and J. S. Cullor. 1993. Purification, primary structures, and antibacterial activities of beta-defensins, a new family of antimicrobial peptides from bovine neutrophils. J. Biol. Chem. 268:66416648.
213. Selsted, M. E.,, Y. Q. Tang,, W. L. Morris,, P. A. McGuire,, M. J. Novotny,, W. Smith,, A. H. Henschen,, and J. S. Cullor. 1996. Purification, primary structures, and antibacterial activities of beta-defensins, a new family of antimicrobial peptides from bovine neutrophils. J. Biol. Chem. 271:16430.
214. Senegas-Balas, F.,, D. Balas,, R. Verger,, A. de Caro,, C. Figarella,, F. Ferrato,, P. Lechene,, C. Bertrand,, and A. Ribet. 1984. Immunohistochemical localization of intestinal phospholipase A2 in rat Paneth cells. Histochemistry 81:581584.
215. Shai, Y. 1999. Mechanism of the binding, insertion and destabilization of phospholipid bilayer membranes by alpha-helical antimicrobial and cell non-selective membrane-lytic peptides. Biochim. Biophys. Acta 1462:5570.
216. Shimada, O.,, H. Ishikawa,, H. Tosaka-Shimada,, T. Yasuda,, K. Kishi,, and S. Suzuki. 1998. Detection of deoxyribonuclease I along the secretory pathway in Paneth cells of human small intestine. J. Histochem. Cytochem. 46:833840.
217. Shirafuji, Y.,, T. Oono,, H. Kanzaki,, S. Hirakawa,, and J. Arata. 1999. Detection of cryptdin in mouse skin. Clin. Diagn. Lab. Immunol. 6:336340.
218. Shirafuji, Y.,, H. Tanabe,, D. P. Satchell,, A. Henschen-Edman,, C. L. Wilson,, and A. J. Ouellette. 2003. Structural determinants of procryptdin recognition and cleavage by matric metalloproteinase-7. J. Biol. Chem. 278:79107919.
218. Shmakov, A. N.,, J. Bode,, P. J. Kilshaw,, and S. Ghosh. 2000. Diverse patterns of expression of the 67-kD laminin receptor in hu man small intestinal mucosa: potential binding sites for prion proteins? J. Pathol. 191:318322.
219. Shmakov, A. N.,, and T. C. Savidge. 1995. Cellular proliferation in the crypt epithelium of human small intestinal xenografts. Epithel. Cell Biol. 4:104112.
220. Silvey, K. J.,, A. B. Hutchings,, M. Vajdy,, M. M. Petzke,, and M. R. Neutra. 2001. Role of immunoglobulin A in protection against reovirus entry into murine Peyer’s patches. J. Virol. 75:1087010879.
221. Simon, T. C.,, and J. I. Gordon. 1995. Intestinal epithelial cell differentiation: new insights from mice, flies and nematodes. Curr. Opin. Genet. Dev. 5:577586.
222. Skalicky, J. J.,, M. E. Selsted,, and A. Pardi. 1994. Structure and dynamics of the neutrophil defensins NP-2, NP-5, and HNP-1: NMR studies of amide hydrogen exchange kinetics. Proteins 20:5267.
223. Sparkes, R. S.,, M. Kronenberg,, C. Heinzmann,, K. A. Daher,, I. Klisak,, T. Ganz,, and T. Mohandas. 1989. Assignment of defensin gene(s) to human chromosome 8p23. Genomics 5:240244.
224. Steiner, H.,, D. Hultmark,, A. Engstrom,, H. Bennich,, and H. G. Boman. 1981. Sequence and specificity of two antibacterial proteins involved in insect immunity. Nature 292:246R