Chapter 10 : Upregulation of Innate Defense Mechanisms by Enteric Infections

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in

Upregulation of Innate Defense Mechanisms by Enteric Infections, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817848/9781555812614_Chap10-1.gif /docserver/preview/fulltext/10.1128/9781555817848/9781555812614_Chap10-2.gif


This chapter examines the role of the intestinal epithelium in innate immune defense against enteric microbial pathogens. It focuses on in vitro and in vivo model systems that can be used to define epithelial cell innate immune defense mechanisms that are activated in response to microbial infection and a spectrum of intestinal epithelial innate defense mechanisms that can be activated by microbial pathogens that use different strategies to interact with the host. Interactions between enteric microbial pathogens and intestinal epithelial cells involve, by definition, two major players: the pathogen and the host epithelial cell. Invasive and noninvasive pathogens can activate epithelial cell signaling cascades that are essential for the development of innate defense. This involves a number of sophisticated evolutionary coevolved strategies on the part of the microbes and the host epithelial cells that are the targets of infection. Relevant to the activation of innate mucosal defense by intestinal epithelial cells, some of the members of one family of pattern-recognition receptors (PRR), the Toll-like receptors (TLR), are expressed by intestinal epithelial cells. Antimicrobial peptides and proteins are highly conserved in evolution and appear to play an important role in intestinal epithelial cell innate defense. Intestinal epithelial cells are an integral component of innate mucosal defense. In this role, they can produce antimicrobial peptides, chemokines, cytokines, nitric oxide (NO), and eicosanoids and express receptors for cytokines and pathogen-associated molecular patterns (PAMP), each of which can play a role in epithelial cell innate defense mechanisms.

Citation: Kagnoff M. 2003. Upregulation of Innate Defense Mechanisms by Enteric Infections, p 155-174. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch10

Key Concept Ranking

Bacterial Proteins
Major Histocompatibility Complex
Immune Systems
Innate Immune System
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

Human intestinal xenograft model. Human fetal intestine (small intestine or colon) is transplanted subcutaneously onto the backs of SCID adult mice and allowed to mature for 10 or more weeks. The mature xenograft contains a fully regenerated intestinal mucosa lined by an epithelium that is of human origin, and the lumen is sterile as assessed by the absence of 16S rRNA. Early epithelial cell signaling events in the xenografts in response to microbial infection can be studied in mice infected intraluminally with human enteric pathogens ( ). In another approach, mice can be injected with human recombinant cytokines known to act on human intestinal epithelial cells to study intestinal epithelial cell signaling events and responses to human mediators in an in vivo model that has an intact human intestinal epithelium ( ). Tissue responses can be studied using histological and molecular approaches. Tissues can also be removed and studied ex vivo (e.g., in modified Ussing chambers).

Citation: Kagnoff M. 2003. Upregulation of Innate Defense Mechanisms by Enteric Infections, p 155-174. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2

Immunohistochemical detection of LL-37/hCAP18 in the epithelium of normal human colon and small intestine. Biopsy specimens from normal human colon (A and B) and proximal human small intestine (C and D) were examined for LL-37/hCAP18 using indirect immunoperoxidase staining. In normal colon, LL37/hCAP18 is expressed mainly by the surface epithelium and adjacent epithelium in the upper crypts (A). There is little or no expression of LL37/hCAP18 in the villus or crypt epithelium in proximal small intestine (C), although in some specimens staining is seen in duodenal Brunner's glands (not shown).

Citation: Kagnoff M. 2003. Upregulation of Innate Defense Mechanisms by Enteric Infections, p 155-174. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3

DC may sample luminal microbes. In this model, epithelial cells are proposed to produce CCL20 (MIP3α) that can chemoattract DC, a key cell type required for antigen presentation to T cells. DC subsequently send out dendrites that cross the epithelial layer and extend into the intestinal lumen where they can sample luminal bacteria. The passage of dendrites across the epithelium is thought to involve an unsealing and resealing of epithelial cell tight junctions and involves interactions between proteins expressed by DC and intestinal epithelial cells (e.g., occludin, claudin-1, JAM) ( ).

Citation: Kagnoff M. 2003. Upregulation of Innate Defense Mechanisms by Enteric Infections, p 155-174. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 4

Epithelial cells produce mediators and express receptors important in innate and adaptive mucosal immunity.

Citation: Kagnoff M. 2003. Upregulation of Innate Defense Mechanisms by Enteric Infections, p 155-174. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Alexopoulou, L.,, A. C. Holt,, R. Medzhitov,, and R. A. Flavell. 2001. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413:732738.
2. Aliprantis, A.,, R.-B. Yang,, M. Mark,, S. Suggett,, B. Devaux,, J. Radolf,, G. Klimpel,, P. Godowski,, and A. Zychlinsky. 1999. Cell activation and apoptosis by bacterial lipoproteins through Toll-like receptor-2. Science 285:736739.
3. Arbibe, L.,, J. P. Mira,, N. Teusch,, L. Kline,, M. Guha,, N. Mackman,, P. J. Godowski,, R. J. Ulevitch,, and U. G. Knaus. 2000. Toll-like receptor 2-mediated NF-κB activation requires a Rac1-dependent pathway. Nat. Immunol. 1:533540.
4. Baba, M.,, T. Imai,, M. Nishimura,, M. Kakizaki,, S. Takagi,, K. Hieshima,, H. Nomiyama,, and O. Yoshie. 1997. Identification of CCR6, the specific receptor for a novel lymphocyte-directed CC chemokine LARC. J. Biol. Chem. 272:1489314898.
5. Bach, S.,, A. Makristathis,, M. Rotter,, and A. M. Hirschl. 2002. Gene expression profiling in AGS cells stimulated with Helicobacter pylori isogenic strains (cagA positive or cagA negative). Infect. Immun. 70:988992.
6. Baeuerle, P. A.,, and T. Henkel. 1994. Function and activation of NF-kB in the immune system. Annu. Rev. Immunol. 12:141179.
7. Barnes, P. J.,, and M. Karin. 1997. NF-κB— a pivotal transcription factor in chronic inflammatory diseases. New Engl. J. Med. 336:10661071.
8. Berin, M. C.,, M. B. Dwinell,, L. Eckmann,, and M. F. Kagnoff. 2001. Production of MDC/CCL22 by human intestinal epithelial cells. Am. J. Physiol. Gastrointest. Liver Physiol. 280:G1217G1226.
9. Berin, M. C.,, L. Eckmann,, D. H. Broide,, and M. F. Kagnoff. 2001. Regulated production of the T helper 2-type T-cell chemoattractant TARC by human bronchial epithelial cells in vitro and in human lung xenografts. Am. J. Respir. Cell Mol. Biol. 24:382389.
10. Bertin, J.,, W. J. Nir,, C. M. Fischer,, O. V. Tayber,, P. R. Errada,, J. R. Grant,, J. J. Keilty,, M. L. Gosselin,, K. E. Robison,, G. H. Wong,, M. A. Glucksmann,, and P. S. Di-Stefano. 1999. Human CARD4 protein is a novel CED-4/Apaf-1 cell death family member that activates NF-κB. . J. Biol. Chem. 274:1295512958.
11. Brand, S.,, T. Sakaguchi,, X. Gu,, S. P. Colgan,, and H. C. Reinecker. 2002. Fractalkine-mediated signals regulate cell-survival and immune-modulatory responses in intestinal epithelial cells. Gastroenterology 122:166177.
12. Burns, K.,, J. Clatworthy,, L. Martin,, F. Martinon,, C. Plumpton,, B. Maschera,, A. Lewis,, K. Ray,, J. Tschapp,, and F. Volpe. 2000. Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nat. Cell Biol. 2:346351.
13. Campos, M. A.,, I. C. Almeida,, O. Takeuchi,, S. Akira,, E. P. Valente,, D. O. Procopio,, L. R. Travassos,, J. A. Smith,, D. T. Golenbock,, and R. T. Gazzinelli. 2001. Activation of Toll-like receptor-2 by glycosylphosphatidylinositol anchors from a protozoan parasite. J. Immunol. 167:416423.
14. Cao, Z.,, J. Xiong,, M. Takeuchi,, T. Kurama,, and D. V. Goeddel. 1996. TRAF6 is a signal transducer for interleukin-1. Nature 383: 443446.
15. Cario, E.,, and D. K. Podolsky. 2000. Differential alteration in intestinal epithelial cell expression of Toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect. Immun. 68:70107017.
16. Cario, E.,, I. M. Rosenberg,, S. L. Brandwein,, P. L. Beck,, H. C. Reinecker,, and D. K. Podolsky. 2000. Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing Toll-like receptors. J. Immunol. 164:966972.
17. Chen, X. M.,, S. A. Levine,, P. L. Splinter,, P. S. Tietz,, A. L. Ganong,, C. Jobin,, G. J. Gores,, C. V. Paya,, and N. F. LaRusso. 2001. Cryptosporidium parvum activates nuclear factor κB in biliary epithelia preventing epithelial cell apoptosis. Gastroenterology 120:17741783.
18. Chu, W. M.,, X. Gong,, Z. W. Li,, K. Takabayashi,, H. H. Ouyang,, Y. Chen,, A. Lois,, D. J. Chen,, G. C. Li,, M. Karin,, and E. Raz. 2000. DNA-PKcs is required for activation of innate immunity by immunostimulatory DNA. Cell 103:909918.
19. Chu, W.-M.,, D. Ostertag,, Z.-W. Li,, L. Chang,, Y. Chen,, Y. Hu,, J. Perrault,, and M. Karin. 1999. JNK2 and IKKβ are required for activating the innate response to viral infection. Immunity 11:721731.
20. Colgan, S. P.,, R. M. Hershberg,, G. T. Furuta,, and R. S. Blumberg. 1999. Ligation of intestinal epithelial CD1d induces bioactive IL-10: critical role of the cytoplasmic tail in autocrine signaling. Proc. Natl. Acad. Sci USA 96: 1393813943.
21. Colgan, S. P.,, M. B. Resnick,, C. A. Parkos,, C. Delp-Archer,, D. McGuirk,, A. E. Bacarra,, P. F. Weller,, and J. L. Madara. 1994. IL-4 directly modulates function of a model human intestinal epithelium. J. Immunol.153:21222129.
22. De, Y.,, Q. Chen,, A. P. Schmidt,, G. M. Anderson,, J. M. Wang,, J. Wooters,, J. J. Oppenheim,, and O. Chertov. 2000. LL-37, the neutrophil granule-and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J. Exp. Med. 192:10691074.
23. Delezay, O.,, N. Koch,, N. Yahi,, D. Hammache,, C. Tourres,, C. Tamalet,, and J. Fantini. 1997. Co-expression of CXCR4/fusin and galactosylceramide in the human intestinal epithelial cell line HT-29. AIDS 11:13111318.
24. Denning, T. L.,, N. A. Campbell,, F. Song,, R. P. Garofalo,, G. R. Klimpel,, V. E. Reyes,, and P. B. Ernst. 2000. Expression of IL-10 receptors on epithelial cells from the murine small and large intestine. Int. Immunol. 12:133139.
25. Dunsche, A.,, Y. Acil,, H. Dommisch,, R. Siebert,, J. M. Schroder,, and S. Jepsen. 2002. The novel human beta-defensin-3 is widely expressed in oral tissues. Eur. J. Oral Sci.110:121124.
26. Dwinell, M. B.,, L. Eckmann,, J. D. Leopard,, N. M. Varki,, and M. F. Kagnoff. 1999. Chemokine receptor expression by human intestinal epithelial cells. Gastroenterology 117:359367.
27. Dwinell, M. B.,, N. Lugering,, L. Eckmann,, and M. F. Kagnoff. 2001. Regulated production of interferon-inducible T-cell chemoattractants by human intestinal epithelial cells. Gastroenterology 120:4959.
28. Eckmann, L.,, H. C. Jung,, C. Schurer-Maly,, A. Panja,, E. Morzycka-Wroblewska,, and M. F. Kagnoff. 1993. Differential cytokine expression by human intestinal epithelial cell lines: regulated expression of interleukin 8. Gastroenterology 105:16891697.
29. Eckmann, L.,, M. F. Kagnoff,, and J. Fierer. 1993. Epithelial cells secrete the chemokine interleukin-8 in response to bacterial entry. Infect. Immun. 61:45694574.
30. Eckmann, L.,, F. Laurent,, T. D. Langford,, M. L. Hetsko,, J. R. Smith,, M. F. Kagnoff,, and F. D. Gillin. 2000. Nitric oxide production by human intestinal epithelial cells and competition for arginine as potential determinants of host defense against the lumen-dwelling pathogen Giardia lamblia. J. Immunol. 164:14781487.
31. Eckmann, L.,, M. T. Rudolf,, A. Ptasznik,, C. Schultz,, T. Jiang,, N. Wolfson,, R. Tsien,, J. Fierer,, S. B. Shears,, M. F. Kagnoff,, and A. E. Traynor-Kaplan. 1997. D-myo-Inositol 1,4,5,6-tetrakisphosphate produced in human intestinal epithelial cells in response to Salmonella invasion inhibits phosphoinositide 3-kinase signaling pathways. Proc. Natl. Acad. Sci. USA 94: 1445614460.
32. Eckmann, L.,, J. R. Smith,, M. P. Housley,, M. B. Dwinell,, and M. F. Kagnoff. 2000. Analysis by high density cDNA arrays of altered gene expression in human intestinal epithelial cells in response to infection with the invasive enteric bacteria Salmonella. J. Biol. Chem. 275: 1408414094.
33. Eckmann, L.,, W. F. Stenson,, T. C. Savidge,, D. C. Lowe,, K. E. Barrett,, J. Fierer,, J. R. Smith,, and M. F. Kagnoff. 1997. Role of intestinal epithelial cells in the host secretory response to infection by invasive bacteria. Bacterial entry induces epithelial prostaglandin h synthase-2 expression and prostaglandin E2 and F2α production. J. Clin. Invest. 100:296309.
34. Elewaut, D.,, J. A. DiDonato,, J. M. Kim,, F. Truong,, L. Eckmann,, and M. F. Kagnoff. 1999. NF-κB is a central regulator of the intestinal epithelial cell innate immune response induced by infection with enteroinvasive bacteria. J. Immunol. 163:14571466.
35. Fish, S. M.,, R. Proujansky,, and W. W. Reenstra. 1999. Synergistic effects of interferon γ and tumour necrosis factor α on T84 cell function. Gut 45:191198.
36. Fitzgerald, K. A.,, E. M. Palsson-McDermott,, A. G. Bowie,, C. A. Jefferies,, A. S. Mansell,, G. Brady,, E. Brint,, A. Dunne,, P. Gray,, M. T. Harte,, D. McMurray,, D. E. Smith,, J. E. Sims,, T. A. Bird,, and L. A. O’Neill. 2001. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413:7883.
37. Frye, M.,, J. Bargon,, B. Lembcke,, T. O. Wagner,, and R. Gropp. 2000. Differential expression of human α-and β-defensins mRNA in gastrointestinal epithelia. Eur. J. Clin. Invest. 30: 695701.
38. Gaillard, J. L.,, P. Berche,, C. Frehel,, E. Gouin,, and P. Cossart. 1991. Entry of L. monocytogenes into cells is mediated by internalin, a repeat protein reminiscent of surface antigens from gram-positive cocci. Cell 65:11271141.
39. Galan, J. E. 2001. Salmonella interactions with host cells: type III secretion at work. Annu. Rev. Cell Dev. Biol. 17:5386.
40. Galan, J. E.,, and A. Collmer. 1999. Type III secretion machines: bacterial devices for protein delivery into host cells. Science 284:13221328.
41. Garcia, J. R.,, F. Jaumann,, S. Schulz,, A. Krause,, J. Rodriguez-Jimenez,, U. Forssmann,, K. Adermann,, E. Kluver,, C. Vogelmeier,, D. Becker,, R. Hedrich,, W. G. Forssmann,, and R. Bals. 2001. Identification of a novel, multifunctional β-defensin (human β-defensin 3) with specific antimicrobial activity. Its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction. Cell Tissue Res. 306:257264.
42. Gasperini, S.,, M. Marchi,, F. Calzetti,, C. Laudanna,, L. Vicentini,, H. Olsen,, M. Murphy,, F. Liao,, J. Farber,, and M. A. Cassatella. 1999. Gene expression and production of the monokine induced by IFN-γ (MIG), IFN-inducible T cell α chemoattractant (I-TAC), and IFN-γ-inducible protein-10 (IP-10) chemokines by human neutrophils. J. Immunol. 162:49284937.
43. Gewirtz, A. T.,, T. A. Navas,, S. Lyons,, P. J. Godowski,, and J. L. Madara. 2001. Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J. Immunol. 167:18821885.
44. Gewirtz, A. T.,, P. O. Simon, Jr.,, C. K. Schmitt,, L. J. Taylor,, C. H. Hagedorn,, A. D. O’Brien,, A. S. Neish,, and J. L. Madara. 2001. Salmonella typhimurium translocates flagellin across intestinal epithelia, inducing a proinflammatory response. J. Clin. Invest. 107: 99109.
45. Girardin, S. E.,, R. Tournebize,, M. Mavris,, A. L. Page,, X. Li,, G. R. Stark,, J. Bertin,, P. S. DiStefano,, M. Yaniv,, P. J. Sansonetti,, and D. J. Philpott. 2001. CARD4/Nod1 mediates NF-kappaB and JNK activation by invasive Shigella flexneri. EMBO Rep. 2:736742.
46. Greaves, D. R.,, W. Wang,, D. J. Dairaghi,, M. C. Dieu,, B. Saint-Vis,, K. Franz-Bacon,, D. Rossi,, C. Caux,, T. McClanahan,, S. Gordon,, A. Zlotnik,, and T. J. Schall. 1997. CCR6, a CC chemokine receptor that interacts with macrophage inflammatory protein 3alpha; and is highly expressed in human dendritic cells. J. Exp. Med. 186:837844.
47. Groh, V.,, A. Steinle,, S. Bauer,, and T. Spies. 1998. Recognition of stress-induced MHC molecules by intestinal epithelial γδ T cells. Science 279:17371740.
48. Hamanaka, Y.,, M. Nakashima,, A. Wada,, M. Ito,, H. Kurazono,, H. Hojo,, Y. Nakahara,, S. Kohno,, T. Hirayama,, and I. Sekine. 2001. Expression of human β-defensin 2 (hBD-2) in Helicobacter pylori induced gastritis: antibacterial effect of hBD-2 against Helicobacter pylori. Gut 49:481487.
49. 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.
50. Hayashi, F.,, K. D. Smith,, A. Ozinsky,, T. R. Hawn,, E. C. Yi,, D. R. Goodlett,, J. K. Eng,, S. Akira,, D. M. Underhill,, and A. Aderem. 2001. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410:10991103.
51. Hemmi, H.,, O. Takeuchi,, T. Kawai,, T. Kaisho,, S. Sato,, H. Sanjo,, M. Matsumoto,, K. Hoshino,, H. Wagner,, K. Takeda,, and S. Akira. 2000. A Toll-like receptor recognizes bacterial DNA. Nature 408:740745.
52. Hersh, D.,, D. M. Monack,, M. R. Smith,, N. Ghori,, S. Falkow,, and A. Zychlinsky. 1999. The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. Proc. Natl. Acad. Sci. USA 96:23962401.
53. Hilbi, H.,, J. E. Moss,, D. Hersh,, Y. Chen,, J. Arondel,, S. Banerjee,, R. A. Flavell,, J. Yuan,, P. J. Sansonetti,, and A. Zychlinsky. 1998. Shigella-induced apoptosis is dependent on caspase-1 which binds to IpaB. J. Biol. Chem. 273:3289532900.
54. Hobbie, S.,, L. M. Chen,, R. J. Davis,, and J. E. Galan. 1997. Involvement of mitogen-activated protein kinase pathways in the nuclear responses and cytokine production induced by Salmonella typhimurium in cultured intestinal epithelial cells. J. Immunol. 159:55505559.
55. Horng, T.,, G. M. Barton,, and R. Medzhitov. 2001. TIRAP: an adapter molecule in the Toll signaling pathway. Nat. Immunol. 2:835841.
56. Huang, G. T.,, L. Eckmann,, T. C. Savidge,, and M. F. Kagnoff. 1996. Infection of human intestinal epithelial cells with invasive bacteria upregulates apical intercellular adhesion molecule-1 (ICAM-1) expression and neutrophil adhesion. J. Clin. Invest. 98:572583.
57. Inohara, N.,, Y. Ogura,, F. F. Chen,, A. Muto,, and G. Nunez. 2001. Human Nod1 confers responsiveness to bacterial lipopolysaccharides. J. Biol. Chem. 276:25512554.
58. Izadpanah, A.,, M. B. Dwinell,, L. Eckmann,, N. M. Varki,, and M. F. Kagnoff. 2001. Regulated MIP-3alpha;/CCL20 production by human intestinal epithelium: mechanism for modulating mucosal immunity. Am. J. Physiol. Gastrointest. Liver Physiol. 280:G710G719.
59. Janeway, C. A., Jr. 1992. The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol. Today 13:1116.
60. Jordan, N. J.,, G. Kolios,, S. E. Abbot,, M. A. Sinai,, D. A. Thompson,, K. Petraki,, and J. Westwick. 1999. Expression of functional CXCR4 chemokine receptors on human colonic epithelial cells. J. Clin. Invest. 104:10611069.
61. Jung, H. C.,, L. Eckmann,, S. K. Yang,, A. Panja,, J. Fierer,, E. Morzycka-Wroblewska,, and M. F. Kagnoff. 1995. A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J. Clin. Invest. 95:5565.
62. Kagnoff, M. F.,, and L. Eckmann. 2001. Analysis of host responses to microbial infection using gene expression profiling. Curr. Opin. Microbiol. 4:246250.
63. Karin, M.,, and Y. Ben-Neriah. 2000. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18:621663.
64. Karin, M.,, and A. Lin. 2002. NF-κB at the crossroads of life and death. Nat. Immunol. 3:221227.
65. Keates, A. C.,, S. Keates,, J. H. Kwon,, K. O. Arseneau,, D. J. Law,, L. Bai,, J. L. Merchant,, T. C. Wang,, and C. P. Kelly. 2001. ZBP-89, Sp1, and nuclear factor-κ B regulate epithelial neutrophil-activating peptide-78 gene expression in Caco-2 human colonic epithelial cells. J. Biol. Chem. 276:4371343722.
66. Keates, S.,, Y. S. Hitti,, M. Upton,, and C. P. Kelly. 1997. Helicobacter pylori infection activates NF-κB in gastric epithelial cells. Gastroenterology 113:10991109.
67. Keates, S.,, A. C. Keates,, E. Mizoguchi,, A. Bhan,, and C. P. Kelly. 1997. Enterocytes are the primary source of the chemokine ENA-78 in normal colon and ulcerative colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 273:G75G82.
68. Keates, S.,, A. C. Keates,, M. Warny,, R. M. Peek, Jr.,, P. G. Murray,, and C. P. Kelly. 1999. Differential activation of mitogen-activated protein kinases in AGS gastric epithelial cells by cag+ and cag Helicobacter pylori. J. Immunol. 163: 55525559.
69. Kunkel, E. J.,, and E. C. Butcher. 2002. Chemokines and the tissue-specific migration of lymphocytes. Immunity 16:14.
70. Larrick, J. W.,, M. Hirata,, R. F. Balint,, J. Lee,, J. Zhong,, and S. C. Wright. 1995. Human CAP18: a novel antimicrobial lipopolysaccharide-binding protein. Infect. Immun. 63:12911297.
71. Laurent, F.,, L. Eckmann,, T. C. Savidge,, G. Morgan,, C. Theodos,, M. Naciri,, and M. F. Kagnoff. 1997. Cryptosporidium parvum infection of human intestinal epithelial cells induces the polarized secretion of C-X-C chemokines. Infect. Immun. 65:50675073.
72. Lecuit, M.,, S. Dramsi,, C. Gottardi,, M. Fedor-Chaiken,, B. Gumbiner,, and P. Cossart. 1999. A single amino acid in E-cadherin responsible for host specificity towards the human pathogen Listeria monocytogenes. EMBO J. 18: 39563963.
73. Lecuit, M.,, S. Vandormael-Pournin,, J. Lefort,, M. Huerre,, P. Gounon,, C. Dupuy,, C. Babinet,, and P. Cossart. 2001. A transgenic model for listeriosis: role of internalin in crossing the intestinal barrier. Science 292:17221725.
74. Lehrer, R. I.,, and T. Ganz. 2002. Cathelicidins: a family of endogenous antimicrobial peptides. Curr. Opin. Hematol. 9:1822.
75. Lehrer, R. I.,, and T. Ganz. 2002. Defensins of vertebrate animals. Curr. Opin. Immunol. 14: 96102.
76. Li, Q.,, D. Van Antwerp,, F. Mercurio,, K.-F. Lee,, and I. M. Verma. 1999. Severe liver degeneration in mice lacking the IκB kinase 2 gene. Science 284:321325.
77. Li, Z.-W.,, W. Chu,, Y. Hu,, M. Delhase,, T. Deerinck,, M. Ellisman,, R. Johnson,, and M. Karin. 1999. The IKK subunit of IκB kinase (IKK) is essential for NF-κB activation and prevention of apoptosis. J. Exp. Med. 189:18391845.
78. Loetscher, M.,, B. Gerber,, P. Loetscher,, S. A. Jones,, L. Piali,, I. Clark-Lewis,, M. Baggiolini,, and B. Moser. 1996. Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated Tlymphocytes. J. Exp. Med. 184:963969.
79. Luster, A. D. 2002. The role of chemokines in linking innate and adaptive immunity. Curr. Opin. Immunol. 14:129135.
80. Maaser, C.,, L. Eckmann,, G. Paesold,, H. S. Kim,, and M. F. Kagnoff. 2002. Ubiquitous production of macrophage migration inhibitory factor by human gastric and intestinal epithelium. Gastroenterology 122:667680.
81. McCole, D. F.,, L. Eckmann,, F. Laurent,, and M. F. Kagnoff. 2000. Intestinal epithelial cell apoptosis following Cryptosporidium parvum infection. Infect. Immun. 68:17101713.
82. Medzhitov, R. 2001. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1:135145.
83. Mengaud, J.,, H. Ohayon,, P. Gounon,, R. M. Mege,, and P. Cossart. 1996. E-cadherin is the receptor for internalin, a surface protein required for entry of L. monocytogenes into epithelial cells. Cell 84:923932.
84. Monack, D. M.,, J. Mecsas,, D. Bouley,, and S. Falkow. 1998. Yersinia-induced apoptosis in vivo aids in the establishment of a systemic infection of mice. J. Exp. Med. 188:21272137.
85. Muzio, M.,, J. Ni,, P. Feng,, and V. M. Dixit. 1997. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278:16121615.
86. Norris, F. A.,, M. P. Wilson,, T. S. Wallis,, E. E. Galyov,, and P. W. Majerus. 1998. SopB, a protein required for virulence of Salmonella dublin, is an inositol phosphate phosphatase. Proc. Natl. Acad. Sci. USA 95:1405714059.
87. Olson, T. S.,, and K. Ley. 2002. Chemokines and chemokine receptors in leukocyte trafficking. Am. J. Physiol. Regul. Integr. Comp. Physiol. 283:R7R28.
88. 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 β-defensins by gastric epithelial cells in response to infection with Helicobacter pylori or stimulation with interleukin-1. Infect. Immun. 68:54125415.
89. 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 κ-defensins hBD-1 and hBD-2 in intestinal epithelium. J. Immunol. 163:67186724.
90. Orth, K.,, Z. Xu,, M. B. Mudgett,, Z. Q. Bao,, L. E. Palmer,, J. B. Bliska,, W. F. Mangel,, B. Staskawicz,, and J. E. Dixon. 2000. Disruption of signaling by Yersinia effector YopJ, a ubiquitin-like protein protease. Science 290:15941597.
91. Ouellette, A. J.,, and C. L. Bevins. 2001. Paneth cell defensins and innate immunity of the small bowel. Inflamm. Bowel Dis. 7:4350.
92. Poltorak, A.,, X. He,, I. Smirnova,, M.-Y. Liu,, C. Van Huffel,, X. Du,, D. Birdwell,, E. Alejos,, M. Silva,, C. Galanos,, M. Freudenberg,, P. Ricciardi-Castagnoli,, B. Layton,, and B. Beutler. 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:20822088.
93. Qin, S.,, J. B. Rottman,, P. Myers,, N. Kassam,, M. Weinblatt,, M. Loetscher,, A. E. Koch,, B. Moser,, and C. R. Mackay. 1998. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J. Clin. Invest. 101:746754.
94. Reinecker, H. C.,, R. P. MacDermott,, S. Mirau,, A. Dignass,, and D. K. Podolsky. 1996. Intestinal epithelial cells both express and respond to interleukin 15. Gastroenterology 111: 17061713.
95. Reinecker, H. C.,, and D. K. Podolsky. 1995. Human intestinal epithelial cells express functional cytokine receptors sharing the common γ c chain of the interleukin 2 receptor. Proc. Natl. Acad. Sci. USA 92:83538357.
96. Rescigno, M.,, G. Rotta,, B. Valzasina,, and P. Ricciardi-Castagnoli. 2001. Dendritic cells shuttle microbes across gut epithelial monolayers. Immunobiology 204:572581.
97. Rescigno, M.,, M. Urbano,, B. Valzasina,, M. Francolini,, G. Rotta,, R. Bonasio,, F. Granucci,, J. P. Kraehenbuhl,, and P. Ricciardi-Castagnoli. 2001. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat. Immunol. 2:361367.
98. Rosenberger, C. M.,, A. J. Pollard,, and B. B. Finlay. 2001. Gene array technology to determine host responses to Salmonella. Microbes Infect. 3:13531360.
99. Rothwarf, D. M.,, and M. Karin. 1999. The NF-kB activation pathway: a paradigm in information transfer from membrane to nucleus. Science’s STKE. www.stke.org/cgi/content/fullOC_sigtrans;1999/5/re1.
100. Sansonetti, P. J.,, J. Arondel,, M. Huerre,, A. Harada,, and K. Matsushima. 1999. Interleukin-8 controls bacterial transepithelial translocation at the cost of epithelial destruction in experimental shigellosis. Infect. Immun. 67:14711480.
101. Savidge, T. C.,, D. C. Lowe,, and W. A. Walker. 2001. Developmental regulation of intestinal epithelial hydrolase activity in human fetal jejunal xenografts maintained in severe-combined immunodeficient mice. Pediatr. Res. 50:196202.
102. Savkovic, S. D.,, A. Koutsouris,, and G. Hecht. 1997. Activation of NF-κB in intestinal epithelial cells by enteropathogenic Escherichia coli. Am. J. Physiol. 273:C1160C1167.
103. Savkovic, S. D.,, A. Ramaswamy,, A. Koutsouris,, and G. Hecht. 2001. EPEC-activated ERK1/2 participate in inflammatory response but not tight junction barrier disruption. Am. J. Physiol. Gastrointest. Liver Physiol. 281:G890G898.
104. Schutte, B. C.,, J. P. Mitros,, J. A. Bartlett,, J. D. Walters,, H. P. Jia,, M. J. Welsh,, T. L. Casavant,, and P. B. McCray, Jr. 2002. Discovery of five conserved β-defensin gene clusters using a computational search strategy. Proc. Natl. Acad. Sci. USA 99:21292133.
105. Shibahara, T.,, J. N. Wilcox,, T. Couse,, and J. L. Madara. 2001. Characterization of epithelial chemoattractants for human intestinal intraepithelial lymphocytes. Gastroenterology 120: 6070.
106. Sierro, F.,, B. Dubois,, A. Coste,, D. Kaiserlian,, J. P. Kraehenbuhl,, and J. C. Sirard. 2001. Flagellin stimulation of intestinal epithelial cells triggers CCL20-mediated migration of dendritic cells. Proc. Natl. Acad. Sci. USA 98: 1372213727.
107. Steiner, T. S.,, J. P. Nataro,, C. E. Poteet-Smith,, J. A. Smith,, and R. L. Guerrant. 2000. Enteroaggregative Escherichia coli expresses a novel flagellin that causes IL-8 release from intestinal epithelial cells. J. Clin. Invest. 105: 17691777.
108. Steinle, A.,, V. Groh,, and T. Spies. 1998. Diversification, expression, and γδ T cell recognition of evolutionarily distant members of the MIC family of major histocompatibility complex class I-related molecules. Proc. Natl. Acad. Sci. USA 95:1251012515.
109. Takeuchi, O.,, K. Hoshino,, T. Kawai,, H. Sanjo,, H. Takada,, T. Ogawa,, K. Takeda,, and S. Akira. 1999. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 11:443451.
110. Takeuchi, O.,, A. Kaufmann,, K. Grote,, T. Kawai,, K. Hoshino,, M. Morr,, P. F. Muhlradt,, and S. Akira. 2000. Cutting edge: preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a Toll-like receptor 2-and MyD88-dependent signaling pathway. J. Immunol. 164:554557.
111. Tesh, V. L.,, and A. D. O’Brien. 1991. The pathogenic mechanisms of Shiga toxin and the Shiga-like toxins. Mol. Microbiol. 5:18171822.
112. Underhill, D. M.,, A. Ozinsky,, K. D. Smith,, and A. Aderem. 1999. Toll-like receptor-2 mediates mycobacteria-induced proinflammatory signaling in macrophages. Proc. Natl. Acad. Sci. USA 96:1445914463.
113. Vallance, B. A.,, and B. B. Finlay. 2000. Exploitation of host cells by enteropathogenic Escherichia coli. Proc. Natl. Acad. Sci. USA 97: 87998806.
114. Varilek, G. W.,, G. A. Neil,, and W. P. Bishop. 1994. Caco-2 cells express type I interleukin-1 receptors: ligand binding enhances proliferation. Am. J. Physiol. 267:G1101G1107.
115. Weinrauch, Y.,, and A. Zychlinsky. 1999. The induction of apoptosis by bacterial pathogens. Annu. Rev. Microbiol. 53:155187.
116. Wesche, H.,, W. J. Henzel,, W. Shillinglaw,, S. Li,, and Z. Cao. 1997. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7:837847.
117. Witthoft, T.,, L. Eckmann,, J. M. Kim,, and M. F. Kagnoff. 1998. Enteroinvasive bacteria directly activate expression of iNOS and NO production in human colon epithelial cells. Am. J. Physiol. 275:G564G571.
118. Yamada, K.,, M. Shimaoka,, K. Nagayama,, T. Hiroi,, H. Kiyono,, and T. Honda. 1997. Bacterial invasion induces interleukin-7 receptor expression in colonic epithelial cell line, T84. Eur. J. Immunol. 27:34563460.
119. Yang, S. K.,, L. Eckmann,, A. Panja,, and M. F. Kagnoff. 1997. Differential and regulated expression of C-X-C, C-C, and C-chemokines by human colon epithelial cells. Gastroenterology 113:12141223.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error