腸道黏膜平時暴露在各種來自於食物的蛋白質之中，是抗原進入體內最主要的場所。然而絕大部分的抗原對人體是無害的，如何避免對於這些抗原產生不必要的免疫反應相當重要。體內具有一種非抗原專一性的免疫調節機制，是由COX-2代謝產物所媒介的，其中包含PGE2。PGE2已被發現能夠經由多種作用抑制發炎性Th1細胞的活化而達到免疫調節能力。本實驗使用Wistar大鼠，發現其腸道固有層單核細胞以及腸繫膜單核細胞在非病理狀態即具有COX-2的表現，並且在非選擇性COX抑制劑Indomethacin倂用食用抗原lysozyme處理7天後發現結腸中CD4細胞增加。另外在選擇性COX-2抑制劑Celecoxib倂用抗原處理7天後發現腸繫膜單核細胞凋亡受到抑制，同時也導致結腸中CD4細胞增加。以上結果顯示COX抑制劑降低腸道對抗原的耐受性，使CD4細胞受到抗原活化而增加，而結腸並未產生自發性腸炎，全身性免疫平衡也未受影響。但是在COX抑制劑倂用抗原處理7天後以TNBS誘導結腸炎，卻發現可能導致比單獨誘導結腸炎發生更嚴重的發炎反應。因此長期使用COX抑制劑的病患可能會造成腸道免疫平衡的改變，若遭受發炎性壓力，可能會加重發炎反應的進程。

The gastrointestinal tract is exposed to luminal antigens derived from the diet. Prevention of the development of inflammatory responses to these nonpathogenic antigens is necessary. There is an antigen-nonspecific mechanism to blunt an inflammatory immune response to a dietary antigen. It is mediated by the COX-2-dependent arachidonic acid metabolites, including prostaglandin E2 (PGE2), which is known to have immunomodulatory effects to down-regulate Th1 response. In this research, COX-2 expression in the laminar propria mononuclear cell and mesenteric mononuclear cell was found in non-pathologic rats. Indomethacin, a non-selective COX inhibitor, inhibited the synthesis of PGE2 in these rats, that received with lysozyme in drinking water. The effects of NSAIDs on the development of the intestinal immune response to a dietary antigen were then performed. After 7-day of daily administration of lysozyme and indomethacin, increased CD4 cell was found in the colon. Celecoxib, a selective COX-2 inhibitor, decreased apoptosis in the mesenteric lymphocytes but increased CD4 cell in the colon. No inflammation was observed in the colon. Experimental colitis were then induced in these rats. Intrarectal instillation of TNBS characterized Th1-dominant inflammation was achieved in colitic rats. Higher myeloperoxidase level and larger amount of Th1 cell infiltration were observed in rats with indomethacin/lysozyme and celecoxib/lysozyme pretreatment. In conclusion, NSAIDs may alter the intestinal immune response to dietary antigens and influence the progress of the intestinal inflammation.

Aabakken L and Osnes M. Non-steroidal anti-inflammatory drug-induced disease in the distal ileum and large bowel. Scand. J. Gastroenterol. Suppl. 163:48–55 (1989).

Bazan NG and Allan G. Platelet-activating factor in the modulation of excitatory amino acid neurotransmitter release and of gene expression. J Lipid Mediat Cell Signal. 14:321-30 (1996).

Berlin C, Berg EL, Briskin MJ, Andrew DP, Kilshaw PJ, Holzmann B, Weissman IL, Hamann A and Butcher EC. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 74:185–195 (1993).

Bjarnason I, Hayllar J, MacPherson AJ and Russell AS. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 104:1832–1847 (1993).

Boise LH, Minn AJ, Noel PJ, June CH, Accavitti MA, Lindsten T and Thompson CB. CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. Immunity 3:87–98 (1995).

Canavan C, Abrams KR and Mayberry J. Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn's disease. Aliment Pharmacol Ther. 23:1097-104 (2006).

Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS and Simmons DL. COX-3, a cyclooxygenase-1 variant inhibited
by acetaminophen and other analgesic/antipyretic drugs:
cloning, structure, and expression. Proc Natl Acad Sci U S A
99:13926–13931 (2002).

Chun KS and Surh YJ. Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention. Biochem Pharmacol. 68:1089-100 (2004).

Cobrin GM and Abreu MT. Defects in mucosal immunity leading to Crohn's disease. Immunol Rev. 206:277-95 (2005).

Eaden J. Review article: colorectal carcinoma and inflammatory bowel disease. Aliment Pharmacol Ther. 20 Suppl 4:24-30 (2004).

Eliopoulos AG, Dumitru CD, Wang CC, Cho J and Tsichlis PN. Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals. EMBO J. 21:4831–4840 (2002).

Elson CO, Sartor RB, Tennyson GS and Riddell RH. Experimental models of inflammatory bowel disease. Gastroenterology 109:1344-67 (1995).

Fujimura Y, Kamoi R and Iida M. Pathogenesis of aphthoid ulcers in Crohn’s disease: correlative findings by magnifying colonoscopy, electron microscopy, and immunohistochemistry. Gut 38:724–732 (1996).

Gaya DR, Russell RK, Nimmo ER and Satsangi J. New genes in inflammatory bowel disease: lessons for complex diseases? Lancet. 367:1271-84 ( 2006).

Glas J, Torok HP, Tonenchi L, Kapser J, Schiemann U, Muller-Myhsok B, Folwaczny M and Folwaczny C. Association of polymorphisms in the interleukin-18 gene in patients with Crohn's disease depending on the CARD15/NOD2 genotype. Inflamm Bowel Dis. 11:1031-7 (2005).

Hamann A, Andrew DP, Jablonski-Westrich D, Holzmann B and Butcher EC. Role of alpha 4-integrins in lymphocyte homing to mucosal tissues in vivo. J Immunol. 152:3282–3293(1994)

Hanauer SB. Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis. 12 Suppl 1:S3-9 (2006).

Hjelmstrom P. Lymphoid neogenesis: de novo formation of lymphoid tissue in chronic inflammation through expression of homing
chemokines. J Leukoc Biol. 69:331–339 (2001).

Ina K, Itoh J, Fukushima K, Kusugami K, Yamaguchi T, Kyokane K, Imada A, Binion DG, Musso A, West GA, Dobrea GM, McCormick TS, Lapetina EG, Levine AD, Ottaway CA and Fiocchi C. Resistance of Crohn's disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance. J Immunol. 163:1081-90 (1999).

Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C and Song SY. Retinoic acid imprints gut-homing specificity on T cells. Immunity. 21:527–538 (2004).

Jess T, Loftus EV Jr, Velayos FS, Harmsen WS, Zinsmeister AR, Smyrk TC, Schleck CD, Tremaine WJ, Melton LJ 3rd, Munkholm P and Sandborn WJ. Risk of intestinal cancer in inflammatory bowel disease: a population-based study from olmsted county, Minnesota. Gastroenterology. 130:1039-46 (2006).

Johansson-Lindbom B, Svensson M, Wurbel MA, Malissen B, Marquez G and Agace W. Selective generation of gut tropic T cells in gut-associated lymphoid tissue (GALT): requirement for GALT dendritic cells and adjuvant. J. Exp. Med. 198:963–969 (2003).

Kaiserling E. Newly-formed lymph nodes in the submucosa in chronic inflammatory bowel disease. Lymphology. 34:22–29 (2001).

Kalinski P, Hilkens CM, Snijders A, Snijdewint FG and Kapsenberg ML. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J. Immunol. 159:28–35 (1997).

Kelly E, Won A, Refaeli Y and Van Parijs L. IL-2 and related cytokines can promote T cell survival by activating AKT. J Immunol. 168:597-603 (2002).

Krawisz JE, Sharon P and Stenson WF. Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Assessment of inflammation in rat and hamster models. Gastroenterology 87:1344-50 (1984).

Kunkel D, Kirchhoff D, Nishikawa S, Radbruch A and Scheffold A. Visualization of peptide presentation following oral application
of antigen in normal and Peyer’s patches-deficient mice. Eur J Immunol
33:1292–1301 (2003).

Lev-Ari S, Strier L, Kazanov D, Madar-Shapiro L, Dvory-Sobol H, Pinchuk I, Marian B, Lichtenberg D and Arber N. Celecoxib and curcumin synergistically inhibit the growth of colorectal cancer cells. Clin Cancer Res. 11:6738-44 (2005).

Lobov IB, Rao S, Carroll TJ, Vallance JE, Ito M, Ondr JK, Kurup S, Glass DA, Patel MS, Shu W, Morrisey EE, McMahon AP, Karsenty G and Lang RA. WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature 437:417-21 (2005).

Lockhart-Mummery HE and Morson BC. Crohn’s disease (regional enteritis) of the large intestine and its distinction from ulcerative colitis. Gut 1:87–105 (1960).

Matuk R, Crawford J, Abreu MT, Targan SR, Vasiliauskas EA, Papadakis KA. The spectrum of gastrointestinal toxicity and effect on disease activity of selective cyclooxygenase-2 inhibitors in patients with inflammatory bowel disease. Inflamm Bowel Dis. 10:352-6 (2004).

McGuirk P and Mills KH. Pathogen-specific regulatory T cells provoke a shift in the Th1/Th2 paradigm in immunity to infectious diseases. Trends Immunol. 23:450-5 (2002).

Miyawaki T, Uehara T, Nibu R, Tsuji T, Yachie A, Yonehara S and Taniguchi N. Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood. J. Immunol. 149:3753–58 (1992).

Morham SG, Langenbach R, Mahler J and Smithies O. Characterization of prostaglandin H synthase 2 deficient mice and implications for mechanisms of NSAID action. Adv Exp Med Biol. 407:131–138 (1997).

Morris E, Hart D, Gao L, Tsallios A, Xue SA and Stauss H. Generation of tumor-specific T-cell therapies. Blood Rev. 20:61-9 (2006).

Mueller DL, Seiffert S, FangW and Behrens TW. Differential regulation of bcl- 2 and bcl-x by CD3, CD28, and the IL-2 receptor in cloned CD4+ helper T cells. A model for the long-term survival of memory cells. J. Immunol. 156:1764–71 (1996).

Nakache M, Berg EL, Streeter PR and Butcher EC. The mucosal vascular addressin is a tissue specific endothelial cell adhesion molecule for circulating lymphocytes. Nature 337:179–181 (1989).

Neurath MF, Finotto S, Fuss I, Boirivant M, Galle PR and Strober W. Regulation of T-cell apoptosis in inflammatory bowel disease: to die or not to die, that is the mucosal question. Trends Immunol. 22:21-6 2001.

Newberry RD, Stenson WF and Lorenz RG. Cyclooxygenase-2-dependent arachidonic acid metabolites are essential modulators of the intestinal immune response to dietary antigen. Nat Med. 5:900-6 (1999).

Newberry RD and Lorenz RG. Organizing a mucosal defense. Immunol Rev. 206:6-21 (2005).

Novak TJ and Rothenberg EV. cAMP inhibits induction of interleukin 2 but not of interleukin 4 in T cells. Proc. Natl. Acad. Sci. USA 87:9353 (1990).

Picker LJ, Kishimoto TK, Smith CW, Warnock RA and Butcher EC. ELAM-1 is an adhesion molecule for skin-homing T cells. Nature 349: 796–798 (1991).

Ria F, Gallard A, Gabaglia CR, Guery JC, Sercarz EE and Adorini L. Selection of similar naive T cell repertoires but induction of distinct T cell responses by native and modified antigen. J Immunol. 172:3447-53 (2004).

Sacks GP, Redman CW and Sargent IL. Monocytes are primed to produce the Th1 type cytokine IL-12 in normal human pregnancy: an intracellular flow cytometric analysis of peripheral blood mononuclear cells. Clin Exp Immunol. 131:490-7 (2003).

Saito S, Sakai M, Sasaki Y, Tanebe K, Tsuda H and Michimata T. Quantitative analysis of peripheral blood Th0, Th1, Th2 and the Th1:Th2 cell ratio during normal human pregnancy and preeclampsia. Clin Exp Immunol. 117:550-5 (1999).

Santucci L, Wallace J, Mencarelli A, Farneti S, Morelli A and Fiorucci S.
Different sensitivity of lamina propria T-cell subsets to nitric oxide-induced apoptosis explains immunomodulatory activity of a nitric oxide-releasing derivative of mesalamine in rodent colitis. Gastroenterology 128:1243-57(2005).

Savill J, Dransfield I, Gregory C and Haslett C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol. 2:965-75 (2002).

Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH and Peter ME. Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 17:1675–1687 (1998).

Scaffidi C, Kirchhoff S, Krammer PH and Peter ME. Apoptosis signaling in lymphocytes. Curr Opin Immunol. 11: 277–285 (1999).

Schieferdecker HL, Ullrich R, Weiss-Breckwoldt AN, Schwarting R, Stein H, Riecken EO and Zeitz M. The HML-1 antigen of intestinal lymphocytes is an activation antigen. J Immunol. 144:2541-2549 (1990).
Singer II, Kawka DW, Schloemann S, Tessner T, Riehl T and Stenson WF. Cyclooxygenase 2 is induced in colonic epithelial cells in inflammatory bowel disease. Gastroenterology. 115:297-306 (1998).

Sinicrope FA and Gill S. Role of cyclooxygenase-2 in colorectal cancer. Cancer Metastasis Rev. 23:63-75 (2004).

Snyder DS, Beller DI and Unanue ER. Prostaglandins modulate macrophage Ia expression. Nature 299:163–165 (1982).

Stallmach A, Marth T, Adrian N, Wittig BM, Ecker KW, Schilling M, and Zeitz M. Increased expression of interleukin-12 receptor beta(2) on lamina propria mononuclear cells of patients with active Crohn's disease. Int J Colorectal Dis. 17:303-10 (2002).

Strober W, Murray PJ, Kitani A and Watanabe T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol. 6:9-20 (2006).

Svensson M, Marsal J, Ericsson A, Carramolino L, Broden T, Marquez G and Agace WW. CCL25 mediates the localization of recently activated CD8abC lymphocytes to the small-intestinal mucosa. J Clin Invest. 110:1113–1121 (2002).

Takeuchi K, Smale S, Premchand P, Maiden L, Sherwood R, Thjodleifsson B, Bjornsson E and Bjarnason I. Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 4:196-202 (2006).

Toth TE, Smith B and Pyle H. Simultaneous separation and purification of mononuclear and polymorphonuclear cells from the peripheral blood of cats. J Virol Methods. 36:185-95 (1992).

Tsune I, Ikejima K, Hirose M, Yoshikawa M, Enomoto N, Takei Y and Sato N. Dietary glycine prevents chemical-induced experimental colitis in the rat. Gastroenterology. 125:775-85(2003).

van der Pouw Kraan TC, Boeije LC, Smeenk RJ, Wijdenes J and Aarden LA. Prostaglandin-E2 is a potent inhibitor of human interleukin 12 production. J Exp Med. 181:775–779 (1995).

Wagner N, Lohler J, Kunkel EJ, Ley K, Leung E, Krissansen G and Rajewsky K, Muller W. Critical role for beta7 integrins in formation of the gut-associated lymphoid tissue. Nature. 382:366–370 (1996).

Strober W, Fuss IJ and Blumberg RS. The immunology of mucosal models of inflammation. Annu Rev Immunol. 20:495–549 (2002).

Wu CY, Wang K, McDyer JF and Seder RA. Prostaglandin E2 and dexamethasone inhibit IL-12 receptor expression and IL-12 responsiveness. J. Immunol. 161:2723–2730 (1998).

Yeung MM, Melgar S, Baranov V, Oberg A, Danielsson A, Hammarstrom S and Hammarstrom ML. Characterisation of mucosal lymphoid aggregates in ulcerative colitis: immune cell phenotype and TcR-gammadelta expression. Gut 47:215–227 (2000).

Yoshino S, Hayashi H, Taneda S, Takano H, Sagai M and Mori Y. Effect of diesel exhaust particle extracts on induction of oral tolerance in mice. Toxicol Sci. 66:293-7 (2002).

Zabel BA, Agace WW, Campbell JJ, Heath HM, Parent D, Roberts AI, Ebert EC, Kassam N, Qin S, Zovko M, LaRosa GJ, Yang LL, Soler D, Butcher EC, Ponath PD, Parker CM and Andrew DP. Human G protein-coupled receptor GPR-9-6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokine-mediated chemotaxis. J Exp Med. 190:1241–1256 (1999).

Zhang J, Cado D, Chen A, Kabra NH and Winoto A. Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature. 392:296–300 (1998).