Chapter 9 : Paneth Cells in Innate Immunity and Intestinal Inflammation

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Paneth cells are specialized intestinal epithelial cells found mainly in the crypts of the small intestine. Paneth cells should be viewed as provisional until they can be confirmed by more specific markers. The presence of antimicrobial proteins in Paneth cells, which are secreted in response to bacterial products, implicates these cells in host defense against infection as part of the innate immune system. Paneth cells are present in the fetal intestine, although numbers are low at birth and increase postnatally, independently of the presence of intestinal microorganisms. The functions of Paneth cells are largely surmised from their repertoire of expressed genes, while direct experimentation has also confirmed a definite role in protection against enteric bacterial infection. In zinc deficiency, Paneth cell morphology is altered, and although metallothionein declines to undetectable levels in most epithelial cells, it can still be detected in the cytoplasm of Paneth cells. The location of Paneth cells adjacent to the stem cell zone of the small intestinal crypts has led to speculation that they play some role in maintaining stem cell function. Necrotizing enterocolitis (NEC) is probably triggered by intestinal infection, and inflammation and ischemia localized to the terminal ileum are prominent pathological features. Expression of antimicrobial genes, and experimental studies showing that Paneth cells respond to bacterial products and are required for enteric host defense, establish them as a significant component of innate immunity in the intestine.

Citation: Keshav S. 2004. Paneth Cells in Innate Immunity and Intestinal Inflammation, p 171-196. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch9
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Image of FIGURE 1

Paneth cells in the small intestinal epithelium. (a) Schematic diagram showing the relationship of crypts to villi and the position of Paneth cells in the base of the crypts. Numerous crypts supply absorptive enterocytes to each villus, which is the major surface for digestion and absorption of nutrients. (b) Cross-sectional diagram showing the relationship of Paneth cells to other cells in the crypt epithelium. Paneth cells occupy the most basal position and migrate toward the base as they differentiate and mature. Stem cells are probably located immediately adjacent to the Paneth cells, and the other intestinal epithelial cell types differentiate and migrate toward the lumen of the intestine and the opening of the crypt. The ultrastructure of Paneth cells is also depicted diagrammatically, showing the prominent rough endoplasmic reticulum, nucleus, Golgi apparatus, and secretory vesicles.

Citation: Keshav S. 2004. Paneth Cells in Innate Immunity and Intestinal Inflammation, p 171-196. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch9
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Image of FIGURE 2

Schematic view of Paneth cell gene expression.The putative functions of various Paneth cell products are depicted. Antibacterial products are secreted apically, where they function to regulate the population of microorganisms in the intestinal lumen. Guanylin released apically may stimulate secretion of chloride ions and water from crypt enterocytes, which express guanylin receptors on their luminal surface. Cytokines and growth factors may be released apically or basolaterally and probably act on adjacent cells in the epithelium and lamina propria. Products such as PLA may be released both apically and basolaterally, and they may be secreted in sufficient amounts to enter the circulation. Cell surface receptors on the Paneth cell membrane may mediate interactions with the products of enteric neurons, inflammatory and immune cells, and bacterial products. PGN, peptidoglycan; 5HT, 5-hydroxy tryptamine; LTA, lipoteichoic acid; VIP, vasoactive intestinal peptide.

Citation: Keshav S. 2004. Paneth Cells in Innate Immunity and Intestinal Inflammation, p 171-196. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch9
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Image of FIGURE 3

Hypothetical model for the pathogenesis of NOD2-mediated Crohn's disease. (a) In the normal intestinal epithelium, Paneth cells respond to microbial stimulation by secreting antibacterial substances that promote a normal balance of intestinal commensals and suppress the growth of pathogens. (b) Defects in the ability of Paneth cells to respond to bacterial stimulation (for example, caused by inherited mutations in the gene) may allow pathogenic bacteria to establish themselves in the intestine. Such bacteria, in turn, may induce inflammation by interaction with epithelial cells and leukocytes, and Paneth cells may exacerbate the resulting pathology by secreting proinflammatory mediators.

Citation: Keshav S. 2004. Paneth Cells in Innate Immunity and Intestinal Inflammation, p 171-196. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch9
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1. Adlakha, H.,, and D. G. Bostwick. 1994. Paneth cell-like change in prostatic adenocarcinoma represents neuroendocrine differentiation: report of 30 cases. Hum. Pathol. 25: 135 139.
2. Ahmad, T.,, A. Armuzzi,, M. Bunce,, K. Mulcahy-Hawes,, S. E. Marshall,, T. R. Orchard,, J. Crawshaw,, O. Large,, A. de Silva,, J. T. Cook,, M. Barnardo,, S. Cullen,, K. I. Welsh,, and D. P. Jewell. 2002. The molecular classification of the clinical manifestations of Crohn's disease. Gastroenterology 122: 854 866.
3. 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: 5397 5403.
4. 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( Part 1): G321 G332.
5. Ariza, A.,, D. Lopez,, E. M. Castella,, C. Munoz,, M. J. Zujar,, and J. L. Mate. 1996. Expression of CD15 in normal and metaplastic Paneth cells of the digestive tract. J. Clin. Pathol. 49: 474 477.
6. Ayabe, T.,, D. P. Satchell,, C. L. Wilson,, W. C. Parks,, M. E. Selsted,, and A. J. Ouellette. 2000. Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat. Immunol. 1: 113 118.
7. Balsinde, J.,, M. A. Balboa,, P. A. Insel,, and E. A. Dennis. 1999. Regulation and inhibition of phospholipase A2. Annu. Rev. Pharmacol. Toxicol. 39: 175 189.
8. Baqui, A. H.,, R. E. Black,, S. El Arifeen,, M. Yunus,, J. Chakraborty,, S. Ahmed,, and J. P. Vaughan. 2002. Effect of zinc supplementation started during diarrhoea on morbidity and mortality in Bangladeshi children: community randomised trial. BMJ 325: 1059.
9. Batlle, E.,, J.T. Henderson,, H. Beghtel,, M. M. van den Born,, E. Sancho,, G. Huls,, J. Meeldijk,, J. Robertson,, M. vandeWetering,, T. Pawson,, and H. Clevers. 2002. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 111: 251 263.
10. Bergenfeldt, M.,, M. Nystrom,, M. Bohe,, C. Lindstrom,, A. Polling,, and K. Ohlsson. 1996. Localization of immunoreactive secretory leukocyte protease inhibitor (SLPI) in intestinal mucosa. J. Gastroenterol. 31: 18 23.
11. Bernet-Camard, M. F.,, M. H. Coconnier,, S. Hudault,, and A. L. Servin. 1996. Differentiationassociated antimicrobial functions in human colon adenocarcinoma cell lines. Exp. Cell Res. 226: 80 89.
12. Bevins, C. L.,, E. Martin-Porter,, and T. Ganz. 1999. Defensins and innate host defence of the gastrointestinal tract. Gut 45: 911 915.
13. Bjerknes, M.,, and H. Cheng. 1981. Methods for the isolation of intact epithelium from the mouse intestine. Anat. Rec. 199: 565 574.
14. Bjerknes, M.,, and H. Cheng. 2001. Modulation of specific intestinal epithelial progenitors by enteric neurons. Proc. Natl. Acad. Sci. USA 98: 12497 12502.
15. Blumberg, R. S. 2001. Characterization of CD1d in mucosal immune function: an immunotherapeutic target for inflammatory bowel disease. Keio J. Med. 50: 39 44.
16. Bohe, M.,, C. Lindstrom,, and K. Ohlsson. 1986. Immunohistochemical demonstration of pancreatic secretory proteins in human paneth cells. Scand. J. Gastroenterol. 126(Supp.): 65 68.
17. Bohe, M.,, C. Lindstrom,, and K. Ohlsson. 1988. Immunoreactive pancreatic secretory trypsin inhibitor in gastrointestinal mucosa. Adv. Exp. Med. Biol. 240: 101 105.
18. Booth, C.,, and C. S. Potten. 2000. Gut instincts: thoughts on intestinal epithelial stem cells. J. Clin. Invest. 105: 1493 1499.
19. 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: 10335 10339.
20. Chung, L. P.,, S. Keshav,, and S. Gordon. 1988. Cloning the human lysozyme cDNA: inverted Alu repeat in the mRNA and in situ hybridization for macrophages and Paneth cells. Proc. Natl. Acad. Sci. USA 85: 6227 6231.
21. Cohen, M.B.,, J.A. Hawkins,, and D. P. Witte. 1998. Guanylin mRNA expression in human intestine and colorectal adenocarcinoma. Lab. Invest. 78: 101 108.
22. Cole, A. M.,, H. I. Liao,, O. Stuchlik,, J. Tilan,, J. Pohl,, and T. Ganz. 2002. Cationic polypeptides are required for antibacterial activity of human airway fluid. J. Immunol. 169: 6985 6991.
23. Cormier, R.T.,, K. H. Hong,, R. B. Halberg,, T. L. Hawkins,, P. Richardson,, R. Mulherkar,, W. F. Dove,, and E. S. Lander. 1997. Secretory phospholipase Pla2g2a confers resistance to intestinal tumorigenesis. Nat. Genet. 17: 88 91.
24. Coutinho, H. B.,, H. C. da Mota,, V. B. Coutinho,, T. I. Robalinho,, A. F. Furtado,, E. Walker,, G. King,, Y. R. Mahida,, H. F. Sewell,, and D. Wakelin. 1998. Absence of lysozyme (muramidase) in the intestinal Paneth cells of newborn infants with necrotising enterocolitis. J. Clin. Pathol. 51: 512 514.
25. Cross, M.,, I. Mangelsdorf,, A. Wedel,, and R. Renkawitz. 1988. Mouse lysozyme M gene: isolation, characterization, and expression studies. Proc. Natl. Acad. Sci. USA 85: 6232 6236.
26. 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( Part 1): G68 G74.
27. de Sauvage, F. J.,, S. Keshav,, W. J. Kuang,, N. Gillett,, W. Henzel,, and D.V. Goeddel. 1992. Precursor structure, expression, and tissue distribution of human guanylin. Proc. Natl. Acad. Sci. USA 89: 9089 9093.
28. Dieckgraefe, B. K.,, D. L. Crimmins,, V. Landt,, C. Houchen,, S. Anant,, R. Porche-Sorbet,, and J. H. Ladenson. 2002. Expression of the regenerating gene family in inflammatory bowel disease mucosa: Reg Ialpha upregulation, processing, and antiapoptotic activity. J. Invest. Med. 50: 421 434.
29. Dietrich, W. F.,, E. S. Lander,, J. S. Smith,, A. R. Moser,, K. A. Gould,, C. Luongo,, N. Borenstein,, and W. Dove. 1993. Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 75: 631 639.
30. Dinsdale, D.,, and B. Biles. 1986. Postnatal changes in the distribution and elemental composition of Paneth cells in normal and corticosteroid-treated rats. Cell Tissue Res. 246: 183 187.
31. Dove, W. F.,, R. T. Cormier,, K. A. Gould,, R. B. Halberg,, A. J. Merritt,, M. A. Newton,, and A. R. Shoemaker. 1998. The intestinal epithelium and its neoplasms: genetic, cellular and tissue interactions. Philos.Trans. R. Soc. London Ser. B 353: 915 923.
32. Eisenhauer, P. B.,, S. S. Harwig,, and R. I. Lehrer. 1992. Cryptdins: antimicrobial defensins of the murine small intestine. Infect. Immun. 60: 3556 3565.
33. Elmes, M. E.,, and J. G. Jones. 1980. Ultrastructural studies on Paneth cell apoptosis in zinc deficient rats. Cell Tissue Res. 208: 57 63.
34. Elmes, M. E.,, and J. G. Jones. 1981. Paneth cell zinc: a comparison of histochemical and microanalytical techniques. Histochem. J. 13: 335 337.
35. Elson, C.O. 2002. Genes, microbes, and T cells—new therapeutic targets in Crohn's disease. N. Engl. J. Med. 346: 614 616.
36. Emmert-Buck, M. R.,, R. F. Bonner,, P. D. Smith,, R. F. Chuaqui,, Z. Zhuang,, S. R. Goldstein,, R. A. Weiss,, and L. A. Liotta. 1996. Laser capture microdissection. Science 274: 998 1001.
37. Erlandsen, S. L.,, and D. G. Chase. 1972a. Paneth cell function: phagocytosis and intracellular digestion of intestinal microorganisms. I. Hexamita muris. J. Ultrastruct. Res. 41: 296 318.
38. Erlandsen, S. L.,, and D. G. Chase. 1972b. Paneth cell function: phagocytosis and intracellular digestion of intestinal microorganisms. II. Spiral microorganism. J. Ultrastruct. Res. 41: 319 333.
39. 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: 1085 1092.
40. Evans, G. S.,, S. Chwalinski,, G. Owen,, C. Booth,, A. Singh,, and C. S. Potten. 1994. Expression of pokeweed lectin binding in murine intestinal Paneth cells. Epithelial. Cell Biol. 3: 7 15.
41. Fiorica-Howells, E.,, R. Hen,, J. Gingrich,, Z. Li,, and M. D. Gershon. 2002. 5-HT(2A) receptors: location and functional analysis in intestines of wildtype and 5-HT(2A) knockout mice. Am. J. Physiol. Gastrointest. Liver Physiol. 282: G877 G893.
42. Fleming, A. 1922. On a remarkable bacteriolytic element found in tissues and secretions. Proc. R. Soc. London B. Ser. 93: 306 317.
43. Fonteles, M. C.,, R. N. Greenberg,, H. S. Monteiro,, M. G. Currie,, and L. R. Forte. 1998. Natriuretic and kaliuretic activities of guanylin and uroguanylin in the isolated perfused rat kidney. Am. J. Physiol. 275( Part 2): F191 F197.
44. Fukui, H.,, Y. Kinoshita,, T. Maekawa,, A. Okada,, S. Waki,, S. Hassan,, H. Okamoto,, and T. Chiba. 1998. Regenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats. Gastroenterology 115: 1483 1493.
45. Ganz, T. 1999. Defensins and host defense. Science 286: 420 421.
46. Ganz, T.,, V. Gabayan,, H. I. Liao,, L. Liu,, A. Oren,, T. Graf,, and A. M. Cole. 2003. Increased inflammation in lysozyme M-deficient mice in response to Micrococcus luteus and its peptidoglycan. Blood 101: 2388 2392.
47. 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: 23729 23740.
48. Garcia-Caballero, T.,, G. Morel,, R. Gallego,, M. Fraga,, E. Pintos,, D. Gago,, B. K. Vonderhaar,, and A. Beiras. 1996. Cellular distribution of prolactin receptors in human digestive tissues. J. Clin. Endocrinol. Metab. 81: 1861 1866.
49. Garrett, K. L.,, M. D. Grounds,, and M. W. Beilharz. 1992. Nonspecific binding of nucleic acid probes to Paneth cells in the gastrointestinal tract with in situ hybridization. J. Histochem. Cytochem. 40: 1613 1618.
50. Ghoos, Y.,, and G. Vantrappen. 1971. The cytochemical localization of lysozyme in Paneth cell granules. Histochem. J. 3: 175 178.
51. Ghosh, D.,, E. Porter,, B. Shen,, S. K. Lee,, D. Wilk,, J. Drazba,, S. P. Yadav,, J.W. Crabb,, T. Ganz,, and C. L. Bevins. 2002. Paneth cell trypsin is the processing enzyme for human defensin-5. Nat. Immunol. 3: 583 590.
52. Glasser, A. L.,, J. Boudeau,, N. Barnich,, M. H. Perruchot,, J. F. Colombel,, and A. Darfeuille-Michaud. 2001. Adherent invasive Escherichia coli strains from patients with Crohn's disease survive and replicate within macrophages without inducing host cell death. Infect. Immun. 69: 5529 5537.
53. Gordon, S.,, J. Todd,, and Z. A. Cohn. 1974. In vitro synthesis and secretion of lysozyme by mononuclear phagocytes. J. Exp. Med. 139: 1228 1248.
54. 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 voltage-gated Ca(2+) channel isoforms in cerebellum, INS-1 cells, and neuroendocrine cells of the digestive system. J. Histochem. Cytochem. 47: 981 994.
55. 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( Part 1): G219 G226.
56. Gronroos, J. O.,, V. J. Laine,, and T. J. Nevalainen. 2002. Bactericidal group IIA phospholipase A2 in serum of patients with bacterial infections. J. Infect. Dis. 185: 1767 1772.
57. Guerrant, R. L.,, M. Kosek,, S. Moore,, B. Lorntz,, R. Brantley,, and A. A. Lima. 2002. Magnitude and impact of diarrheal diseases. Arch. Med. Res. 33: 351 355.
58. Haapamaki, M. M.,, J. M. Gronroos,, H. Nurmi,, K. Alanen,, and T. J. Nevalainen. 1999. Gene expression of group II phospholipase A2 in intestine in Crohn's disease. Am. J. Gastroenterol. 94: 713 720.
59. Harwig, S. S.,, L. Tan,, X. D. Qu,, Y. Cho,, P. B. Eisenhauer,, and R. I. Lehrer. 1995. Bactericidal properties of murine intestinal phospholipase A2. J. Clin. Invest. 95: 603 610.
60. Hausmann, M.,, S. Kiessling,, S. Mestermann,, G. Webb,, T. Spottl,, T. Andus,, J. Scholmerich,, H. Herfarth,, K. Ray,, W. Falk,, and G. Rogler. 2002. Toll-like receptors 2 and 4 are up-regulated during intestinal inflammation. Gastroenterology 122: 1987 2000.
61. 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: 881 884.
62. Hooper, L.V.,, T. S. Stappenbeck,, C.V. Hong,, and J. I. Gordon. 2003. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nat. Immunol. 4: 269 273.
63. Hurley, B. W.,, and C. C. Nguyen. 2002. The spectrum of pseudomembranous enterocolitis and antibiotic-associated diarrhea. Arch. Intern. Med. 162: 2177 2184.
64. Inohara, N.,, Y. Ogura,, A. Fontalba,, O. Gutierrez,, F. Pons,, J. Crespo,, K. Fukase,, S. Inamura,, S. Kusumoto,, M. Hashimoto,, S. J. Foster,, A. P. Moran,, J. L. Fernandez-Luna,, and G. Nunez. 2003. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J. Biol. Chem. 278: 5509 5512.
65. Ivandic, B.,, L. W. Castellani,, X. P. Wang,, J. H. Qiao,, M. Mehrabian,, M. Navab,, A. M. Fogelman,, D. S. Grass,, M. E. Swanson,, M. C. de Beer,, F. de Beer,, and A. J. Lusis. 1999. Role of group II secretory phospholipase A2 in atherosclerosis: 1. Increased atherogenesis and altered lipoproteins in transgenic mice expressing group IIa phospholipase A2. Arterioscler.Thromb.Vasc. Biol. 19: 1284 1290.
66. Jass, J. R.,, V. L. Whitehall,, J. Young,, and B. A. Leggett. 2002. Emerging concepts in colorectal neoplasia. Gastroenterology 123: 862 876.
67. Jewell, D. P. 1998. Ulcerative colitis and Crohn's disease—susceptibility genes and clinical patterns. J. Gastroenterol. 33: 458 462.
68. Kamal, M.,, M. S. Dehlawi,, L. R. Brunet,, and D. Wakelin. 2002. Paneth and intermediate cell hyperplasia induced in mice by helminth infections. Parasitology 125 (Part 3): 275 281.
69. Kamal, M.,, D. Wakelin,, and Y. Mahida. 2001. Mucosal responses to infection with Trichinella spiralis in mice. Parasite J. Soc. Francaise Parasitol. 8( Suppl.): S110 S113.
70. Keren, D. F.,, H. L. Elliott,, G. D. Brown,, and J. H. Yardley. 1975. Atrophy of villi with hypertrophy and hyperplasia of Paneth cells in isolated (thiry-Vella) ileal loops in rabbits. Light-microscopic studies. Gastroenterology 68: 83 93.
71. 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: 327 332.
72. Keshav, S.,, A. J. McKnight,, R. Arora,, and S. Gordon. 1997. Cloning of intestinal phospholipase A2 from intestinal epithelial RNA by differential display PCR. Cell Prolif. 30: 369 383.
73. Kita, T.,, K. Kitamura,, J. Sakata,, and T. Eto. 1999. Marked increase of guanylin secretion in response to salt loading in the rat small intestine. Am. J. Physiol. 277( Part 1): G960 G966.
74. Kiyohara, H.,, H. Egami,, Y. Shibata,, K. Murata,, S. Ohshima,, and M. Ogawa. 1992. Light microscopic immunohistochemical analysis of the distribution of group II phospholipase A2 in human digestive organs. J. Histochem. Cytochem. 40: 1659 1664.
75. Kliegman, R. M. 1990. Models of the pathogenesis of necrotizing enterocolitis. J. Pediatr. 117( Part 2): S2 S5.
76. Kliegman, R. M. 2003. The relationship of neonatal feeding practices and the pathogenesis and prevention of necrotizing enterocolitis. Pediatrics 111: 671 672.
77. Komiya, T.,, Y. Tanigawa,, and S. Hirohashi. 1998. Cloning of the novel gene intelectin, which is expressed in intestinal paneth cells in mice. Biochem. Biophys. Res. Commun. 251: 759 762.
78. Kontoyiannis, D.,, M. Pasparakis,, T.T. Pizarro,, F. Cominelli,, and G. Kollias. 1999. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10: 387 398.
79. Kontoyiannis, D.,, G. Boulougouris,, M. Manoloukos,, M. Armaka,, M. Apostolaki,, T. Pizarro,, A. Kotlyarov,, I. Forster,, R. Flavell,, M. Gaestel,, P. Tsichlis,, F. Cominelli,, and G. Kollias. 2002. Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn's-like inflammatory bowel disease. J. Exp. Med. 196: 1563 1574.
80. Krause, R.,, M. Hemberger,, M. Messerschmid,, W. Mayer,, R. Kothary,, C. Dixkens,, and R. Fundele. 1998. Molecular cloning and characterization of murine Mpgc60, a gene predominantly expressed in the intestinal tract. Differentiation 63: 285 294.
81. Kury, S.,, B. Dreno,, S. Bezieau,, S. Giraudet,, M. Kharfi,, R. Kamoun,, and J. P. Moisan. 2002. Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat. Genet. 31: 239 240.
82. Lacasse, J.,, and L. H. Martin. 1992. Detection of CD1 mRNA in Paneth cells of the mouse intestine by in situ hybridization. J. Histochem. Cytochem. 40: 1527 1534.
83. Laine, V. J.,, D. S. Grass,, and T. J. Nevalainen. 2000. Resistance of transgenic mice expressing human group II phospholipase A2 to Escherichia coli infection. Infect. Immun. 68: 87 92.
84. Lala, S.,, Y. Ogura,, C. Osborne,, S.-Y. Hor,, A. Bromfield,, S. Davies,, O. Ogunbiyi,, G. Nuñez,, and S. Keshav. 2003. Crohn's disease and the NOD2 gene: a role for Paneth cells. Gastroenterology 125: 47 57.
85. Lee, K. R.,, and T. D. Trainer. 1990. Adenocarcinoma of the uterine cervix of small intestinal type containing numerous Paneth cells. Arch. Pathol. Lab. Med. 114: 731 733.
86. 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: 1013 1019.
87. Lehrer, R. I.,, and T. Ganz. 1992. Defensins: endogenous antibiotic peptides from human leukocytes. Ciba Found. Symp. 171: 276 290.
88. Leitinger, N.,, A. D. Watson,, S. Y. Hama,, B. Ivandic,, J. H. Qiao,, J. Huber,, K. F. Faull,, D. S. Grass,, M. Navab,, A. M. Fogelman,, F. C. de Beer,, A. J. Lusis,, and J. A. Berliner. 1999. Role of group II secretory phospholipase A2 in atherosclerosis: 2. Potential involvement of biologically active oxidized phospholipids. Arterioscler.Thromb.Vasc. Biol. 19: 1291 1298.
89. Lencer, W. I. 1998. Paneth cells: on the front line or in the backfield? Gastroenterology 114: 1343 1345.
90. Lewin, K. 1969. The Paneth cell in disease. Gut 10: 804 811.
91. Madden, J. A.,, and J. O. Hunter. 2002. A review of the role of the gut microflora in irritable bowel syndrome and the effects of probiotics. Br. J. Nutr. 88( Suppl. 1): S67 S72.
92. Masciotra, L.,, P. Lechene dela 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: 519 524.
93. Mathan, M.,, J. Hughes,, and R. Whitehead. 1987. The morphogenesis of the human Paneth cell. An immunocytochemical ultrastructural study. Histochemistry 87: 91 96.
94. Mills, J. C.,, and J. I. Gordon. 2001. The intestinal stem cell niche: there grows the neighborhood. Proc. Natl. Acad. Sci. USA 98: 12334 12336.
95. Mirecka, J.,, D. Marx,, and A. Schauer. 1995. Immunohistochemical localization of CD44 variants 5 and 6 in human gastric mucosa and gastric cancer. Anticancer Res. 15: 1459 1465.
96. 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: 9 13.
97. 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: 2022 2034.
98. 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: 43 49.
99. Nakamura, H.,, S. Horita,, N. Senmaru,, Y. Miyasaka,, T. Gohda,, Y. Inoue,, M. Fujita,, T. Meguro,, T. Morita,, and K. Nagashima. 2002. Association of matrilysin expression with progression and poor prognosis in human pancreatic adenocarcinoma. Oncol. Rep. 9: 751 755.
100. Nevalainen, T. J.,, and T. J. Haapanen. 1993. Distribution of pancreatic (group I) and synovial-type (group II) phospholipases A2 in human tissues. Inflammation 17: 453 464.
101. Newell, K. J.,, L.M. Matrisian,, and D. K. Driman. 2002. Matrilysin (matrix metalloproteinase-7) expression in ulcerative colitis-related tumorigenesis. Mol. Carcinog. 34: 59 63.
102. Nyman, K. M.,, W. Uhl,, J. Forsstrom,, M. Buchler,, H. G. Beger,, and T. J. Nevalainen. 1996. Serum phospholipase A2 in patients with multiple organ failure. J. Surg. Res. 60: 7 14.
103. 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. 2001a. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411: 603 606.
104. Ogura, Y.,, N. Inohara,, A. Benito,, F. F. Chen,, S. Yamaoka,, and G. Nunez. 2001b. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J. Biol. Chem. 276: 4812 4818.
105. 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( Part 1): G531 G538.
106. Ouellette, A. J.,, and C. L. Bevins. 2001. Paneth cell defensins and innate immunity of the small bowel. Inflamm. Bowel Dis. 7: 43 50.
107. Ouellette, A. J.,, R. M. Greco,, M. James,, D. Frederick,, J. Naftilan,, and J. T. Fallon. 1989. Developmental regulation of cryptdin, a corticostatin/defensin precursor mRNA in mouse small intestinal crypt epithelium. J. Cell Biol. 108: 1687 1695.
108. Paneth, J. 1888. Ueber die secernirenden Zellen des Dunndarm-Epithels. Arch. Mikroskop. Anat. 31: 113 191.
109. Papadakis, K. A.,, and S. R. Targan. 2000. Tumor necrosis factor: biology and therapeutic inhibitors. Gastroenterology 119: 1148 1157.
110. 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: 757 768.
111. 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: 2396 2401.
112. Porter, E. M.,, C. L. Bevins,, D. Ghosh,, and T. Ganz. 2002. The multifaceted Paneth cell. Cell. Mol. Life Sci. 59: 156 170.
113. Poulsen, S. S.,, E. Nexo,, P. S. Olsen,, J. Hess,, and P. Kirkegaard. 1986. Immunohistochemical localization of epidermal growth factor in rat and man. Histochemistry 85: 389 394.
114. Praml, C.,, L. C. Amler,, S. Dihlmann,, L. H. Finke,, P. Schlag,, and M. Schwab. 1998. Secretory type II phospholipase A2 (PLA2G2A) expression status in colorectal carcinoma derived cell lines and in normal colonic mucosa. Oncogene 17: 2009 2012.
115. Prasad, A. S. 1995. Zinc: an overview. Nutrition 11 (Suppl. 1): 93 99.
116. 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: 801 812.
117. 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: 697 704.
118. Ryan, G. R.,, X. M. Dai,, M. G. Dominguez,, W. Tong,, F. Chuan,, O. Chisholm,, R. G. Russell,, J.W. Pollard,, and E. R. Stanley. 2001. Rescue of the colony-stimulating factor 1 (CSF-1)-nullizygous mouse (Csf1(op)/Csf1(op)) phenotype with a CSF-1 transgene and identification of sites of local CSF-1 synthesis. Blood 98: 74 84.
119. 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: 20 26.
120. Satoh, Y. 1988a. Atropine inhibits the degranulation of Paneth cells in ex-germ-free mice. Cell Tissue Res. 253: 397 402.
121. Satoh, Y. 1988b. Effect of live and heat-killed bacteria on the secretory activity of Paneth cells in germfree mice. Cell Tissue Res. 251: 87 93.
122. Satoh, Y.,, and L. Vollrath. 1986. Quantitative electron microscopic observations on Paneth cells of germfree and ex-germfree Wistar rats. Anat. Embryol. 173: 317 322.
123. Satoh, Y.,, K. Ishikawa,, H. Tanaka,, and K. Ono. 1986a. Immunohistochemical observations of immunoglobulin A in the Paneth cells of germ-free and formerly-germ-free rats. Histochemistry 85: 197 201.
124. Satoh, Y.,, K. Ishikawa,, K. Ono,, and L. Vollrath. 1986b. Quantitative light microscopic observations on Paneth cells of germ-free and ex-germ-free Wistar rats. Digestion 34: 115 121.
125. Satoh, Y.,, K. Ishikawa,, Y. Oomori,, M. Yamano,, and K. Ono. 1989. Effects of cholecystokinin and carbamylcholine on Paneth cell secretion in mice: a comparison with pancreatic acinar cells. Anat. Rec. 225: 124 132.
126. Satoh, Y.,, M. Yamano,, M. Matsuda,, and K. Ono. 1990. Ultrastructure of Paneth cells in the intestine of various mammals. J. Electron. Microsc.Tech. 16: 69 80.
127. Satoh, Y.,, K. Ishikawa,, Y. Oomori,, S. Takeda,, and K. Ono. 1992. Bethanechol and a G-protein activator, NaF/AlCl3, induce secretory response in Paneth cells of mouse intestine. Cell Tissue Res. 269: 213 220.
128. Sawada, M.,, K. Takahashi,, S. Sawada,, and O. Midorikawa. 1991. Selective killing of Paneth cells by intravenous administration of dithizone in rats. Int. J. Exp. Pathol. 72: 407 421.
129. Sazawal, S.,, R. E. Black,, M. K. Bhan,, N. Bhandari,, A. Sinha,, and S. Jalla. 1995. Zinc supplementation in young children with acute diarrhea in India. N. Engl. J. Med. 333: 839 844.
130. Schmauder-Chock, E. A.,, S. P. Chock,, and M. L. Patchen. 1994. Ultrastructural localization of tumour necrosis factor-alpha. Histochem. J. 26: 142 151.
131. Schreiber, S.,, S. Nikolaus,, and J. Hampe. 1998. Activation of nuclear factor kappa B inflammatory bowel disease. Gut 42: 477 484.
132. Schwalbe, G. 1872. Beitrage zur Kenntnis der Drusen in den Darmwandungen, in's Besondere der Brunner'schen Drusen. Arch. Mikroskop. Anat. 8: 92 140.
133. Scott, H.,, and P. Brandtzaeg. 1981. Enumeration of Paneth cells in coeliac disease: comparison of conventional light microscopy and immunofluorescence staining for lysozyme. Gut 22: 812 816.
134. Seno, H.,, M. Sawada,, H. Fukuzawa,, Y. Morita,, S. Takaishi,, H. Hiai,, and T. Chiba. 2001. Enhanced expression of transforming growth factor (TGF)-alpha precursor and TGF-beta1 during Paneth cell regeneration. Dig. Dis. Sci. 46: 1004 1010.
135. Seno, H.,, M. Sawada,, H. Fukuzawa,, Y. Morita-Fujisawa,, S. Takaishi,, H. Hiai,, and T. Chiba. 2002. Involvement of tumor necrosis factor alpha in intestinal epithelial cell proliferation following Paneth cell destruction. Scand. J. Gastroenterol. 37: 154 160.
136. Sheahan, D. G.,, and H. R. Jervis. 1976. Comparative histochemistry of gastrointestinal mucosubstances. Am. J. Anat. 146: 103 131.
137. 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: 833 840.
138. Soga, N.,, R. Suzuki,, and Y. Komeda. 1995. [A case report of prostate cancer with Paneth cell-like change]. Hinyokika Kiyo 41: 891 894.
139. Sohn, K. J.,, S. A. Shah,, S. Reid,, M. Choi,, J. Carrier,, M. Comiskey,, C. Terhorst,, and Y. I. Kim. 2001. Molecular genetics of ulcerative colitis-associated colon cancer in the interleukin 2- and beta(2)-microglobulin-deficient mouse. Cancer Res. 61: 6912 6917.
140. Stamp, G. W.,, R. Poulsom,, L. P. Chung,, S. Keshav,, R. E. Jeffery,, J. A. Longcroft,, M. Pignatelli,, and N. A. Wright. 1992. Lysozyme gene expression in inflammatory bowel disease. Gastroenterology 103: 532 538.
141. Stappenbeck, T. S.,, and J. I. Gordon. 2000. Rac1 mutations produce aberrant epithelial differentiation in the developing and adult mouse small intestine. Development 127: 2629 2642.
142. Stappenbeck, T. S.,, L. V. Hooper,, and J. I. Gordon. 2002. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells. Proc. Natl. Acad. Sci. USA 99: 15451 15455.
143. Strachan, D. P. 2000. Family size, infection and atopy: the first decade of the “hygiene hypothesis.” Thorax 55( Suppl. 1): S2 S10.
144. Szczurek, E. I.,, C. S. Bjornsson,, and C. G. Taylor. 2001. Dietary zinc deficiency and repletion modulate metallothionein immunolocalization and concentration in small intestine and liver of rats. J. Nutr. 131: 2132 2138.
145. Takemori, H.,, F. N. Zolotaryov,, L. Ting,, T. Urbain,, T. Komatsubara,, O. Hatano,, M. Okamoto,, and H. Tojo. 1998. Identification of functional domains of rat intestinal phospholipase B/lipase. Its cDNA cloning, expression, and tissue distribution. J. Biol. Chem. 273: 2222 2231.
146. Takubo, K.,, J. M. Nixon,, and J. R. Jass. 1995. Ducts of esophageal glands proper and paneth cells in Barrett's esophagus: frequency in biopsy specimens. Pathology 27: 315 317.
147. Tan, X.,, W. Hsueh,, and F. Gonzalez-Crussi. 1993. Cellular localization of tumor necrosis factor (TNF)-alpha transcripts in normal bowel and in necrotizing enterocolitis. TNF gene expression by Paneth cells, intestinal eosinophils, and macrophages. Am. J. Pathol. 142: 1858 1865.
148. Tanaka, M.,, H. Saito,, T. Kusumi,, S. Fukuda,, T. Shimoyama,, Y. Sasaki,, K. Suto,, A. Munakata,, and H. Kudo. 2001. Spatial distribution and histogenesis of colorectal Paneth cell metaplasia in idiopathic inflammatory bowel disease. J. Gastroenterol. Hepatol. 16: 1353 1359.
149. Tani, T.,, M. Fujino,, K. Hanasawa,, T. Shimizu,, Y. Endo,, and M. Kodama. 2000. Bacterial translocation and tumor necrosis factor-alpha gene expression in experimental hemorrhagic shock. Crit. Care Med. 28: 3705 3709.
150. Tomlinson, I. P.,, N. E. Beck,, K. Neale,, and W. F. Bodmer. 1996. Variants at the secretory phospholipase A2 (PLA2G2A) locus: analysis of associations with familial adenomatous polyposis and sporadic colorectal tumours. Ann. Hum. Genet. 60(Part 5): 369 376.
151. Trahair, J. F.,, M. R. Neutra,, and J. I. Gordon. 1989. Use of transgenic mice to study the routing of secretory proteins in intestinal epithelial cells: analysis of human growth hormone compartmentalization as a function of cell type and differentiation. J. Cell. Biol. 109(Part 2): 3231 3242.
152. Tsuji, S.,, J. Uehori,, M. Matsumoto,, Y. Suzuki,, A. Matsuhisa,, K. Toyoshima,, and T. Seya. 2001. Human intelectin is a novel soluble lectin that recognizes galactofuranose in carbohydrate chains of bacterial cell wall. J. Biol. Chem. 276: 23456 23463.
153. Tsumura, T.,, A. Hazama,, T. Miyoshi,, S. Ueda,, and Y. Okada. 1998. Activation of cAMP-dependent C1-currents in guinea-pig paneth cells without relevant evidence for CFTR expression. J. Physiol. 512 (Part 3): 765 777.
154. Van Heel, D. A.,, D. P. McGovern,, and D. P. Jewell. 2001. Crohn's disease: genetic susceptibility, bacteria, and innate immunity. Lancet 357: 1902 1904.
155. Wang, T. C.,, J. R. Goldenring,, C. Dangler,, S. Ito,, A. Mueller,, W. K. Jeon,, T. J. Koh,, and J. G. Fox. 1998. Mice lacking secretory phospholipase A2 show altered apoptosis and differentiation with Helicobacter felis infection. Gastroenterology 114: 675 689.
156. Wehkamp, J.,, B. Schwind,, K. R. Herrlinger,, S. Baxmann,, K. Schmidt,, M. Duchrow,, C. Wohlschlager,, A. C. Feller,, E. F. Stange,, and K. Fellermann. 2002. Innate immunity and colonic inflammation: enhanced expression of epithelial alphadefensins. Dig. Dis. Sci. 47: 1349 1355.
157. Wilson, C. L.,, K. J. Heppner,, L.A. Rudolph,, and L. M. Matrisian. 1995. The metalloproteinase matrilysin is preferentially expressed by epithelial cells in a tissue-restricted pattern in the mouse. Mol. Biol. Cell 6: 851 869.
158. Wilson, C. L.,, K. J. Heppner,, P.A. Labosky,, B. L. Hogan,, and L. M. Matrisian. 1997. Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin. Proc. Natl. Acad. Sci. USA 94: 1402 1407.
159. Wilson, C. L.,, A. J. Ouellette,, D. P. Satchell,, T. Ayabe,, Y. S. Lopez-Boado,, J. L. Stratman,, S. J. Hultgren,, L. M. Matrisian,, and W. C. Parks. 1999. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286: 113 117.


Generic image for table

Paneth cell gene expression

Citation: Keshav S. 2004. Paneth Cells in Innate Immunity and Intestinal Inflammation, p 171-196. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch9
Generic image for table

Putative Paneth cell functions

Citation: Keshav S. 2004. Paneth Cells in Innate Immunity and Intestinal Inflammation, p 171-196. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch9

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