Spontaneous and Continuous Cyclooxygenase-2-Dependent Prostaglandin E2 Production by Stromal Cells in the Murine Small Intestine Lamina Propria: Directing the Tone of the Intestinal Immune Response1

The mechanisms allowing the gastrointestinal immune system to avoid an inappropriate inflammatory response to nonpathogenic luminal Ags are poorly understood. We have previously described a role for cyclooxygenase (COX)-2-dependent arachidonic acid metabolites produced by the murine small intestine lamina propria in controlling the immune response to a dietary Ag. To better understand the role of COX-2-dependent arachidonic acid metabolites produced by the lamina propria, we examined the pattern of expression and the cellular source of COX-2 and COX-2-dependent PGE2. We now demonstrate that non-bone marrow-derived lamina propria stromal cells have basal COX-2 expression and that COX-2-dependent PGE2 production by these cells is spontaneous and continuous. The other mucosal and nonmucosal lymphoid compartments examined do not share this phenotype. In contrast to the majority of descriptions of COX-2 expression, COX-2 expression by lamina propria stromal cells is not dependent upon exogenous stimuli, including adhesion, LPS signaling via Toll-like receptor 4, or the proinflammatory cytokines TNF-α, IFN-γ, and IL-1β. These findings, in conjunction with the known immunomodulatory capacities of PGs, suggest that COX-2 expression by the small intestine lamina propria is a basal state contributing to the hyporesponsiveness of the intestinal immune response.

[1]  R. Lorenz,et al.  The gastrointestinal ecosystem: a precarious alliance among epithelium, immunity and microbiota , 2001, Cellular microbiology.

[2]  Macdonald,et al.  Recent Developments in the Immunology of Inflammatory Bowel Disease , 2000, Scandinavian journal of immunology.

[3]  S. Targan,et al.  Role of cytokines in the pathogenesis of inflammatory bowel disease. , 2000, Annual review of medicine.

[4]  C. Nagler‐Anderson.  Tolerance and immunity in the intestinal immune system. , 2000, Critical reviews in immunology.

[5]  R. Garavito,et al.  Cyclooxygenases: structural, cellular, and molecular biology. , 2000, Annual review of biochemistry.

[6]  Fiona Powrie,et al.  An Essential Role for Interleukin 10 in the Function of Regulatory T Cells That Inhibit Intestinal Inflammation , 1999, The Journal of experimental medicine.

[7]  F. Powrie,et al.  Regulatory T cells and inflammatory bowel disease. , 1999, Immunology today.

[8]  R. Lorenz,et al.  Cyclooxygenase-2-dependent arachidonic acid metabolites are essential modulators of the intestinal immune response to dietary antigen , 1999, Nature Medicine.

[9]  A B West,et al.  Myofibroblasts. II. Intestinal subepithelial myofibroblasts. , 1999, American journal of physiology. Cell physiology.

[10]  A B West,et al.  Myofibroblasts: paracrine cells important in health and disease. , 2000, Transactions of the American Clinical and Climatological Association.

[11]  R. N. Smith,et al.  Colitis in transgenic and knockout animals as models of human inflammatory bowel disease , 1999, Immunological reviews.

[12]  D. Gilroy,et al.  Inducible cyclooxygenase may have anti-inflammatory properties , 1999, Nature Medicine.

[13]  G. Kollias,et al.  Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. , 1999, Immunity.

[14]  L. Larivière,et al.  Endotoxin-tolerant Mice Have Mutations in Toll-like Receptor 4 (Tlr4) , 1999, The Journal of experimental medicine.

[15]  D. Powell.  Intestinal subepithelial myofibroblasts , 1999 .

[16]  R. Seder,et al.  Prostaglandin E2 and dexamethasone inhibit IL-12 receptor expression and IL-12 responsiveness. , 1998, Journal of immunology.

[17]  H. Weiner,et al.  In situ immune response in gut-associated lymphoid tissue (GALT) following oral antigen in TCR-transgenic mice. , 1998, Journal of immunology.

[18]  N. Bazan,et al.  Cyclooxygenase 2 RNA message abundance, stability, and hypervariability in sporadic alzheimer neocortex , 1997, Journal of neuroscience research.

[19]  G. Delespesse,et al.  Prostaglandin E2 primes naive T cells for the production of anti‐inflammatory cytokines , 1997, European journal of immunology.

[20]  Hervé Groux,et al.  A CD4+T-cell subset inhibits antigen-specific T-cell responses and prevents colitis , 1997, Nature.

[21]  F. Autschbach,et al.  T cells of the human intestinal lamina propria are high producers of interleukin-10 , 1997, Gut.

[22]  P. Kalinski,et al.  IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. , 1997, Journal of immunology.

[23]  A. Knox,et al.  Effect of interleukin‐1β, tumour necrosis factor‐α and interferon‐γ on the induction of cyclo‐oxygenase‐2 in cultured human airway smooth muscle cells , 1997 .

[24]  D. Powell,et al.  Phenotypic characterization of an intestinal subepithelial myofibroblast cell line. , 1997, The American journal of physiology.

[25]  G. Morrone,et al.  Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. , 1997, Gastroenterology.

[26]  William L. Smith,et al.  Prostaglandin Endoperoxide H Synthases (Cyclooxygenases)-1 and −2* , 1996, The Journal of Biological Chemistry.

[27]  T. Hinterleitner,et al.  IL-1 stimulates intestinal myofibroblast COX gene expression and augments activation of Cl- secretion in T84 cells. , 1996, The American journal of physiology.

[28]  M. Neurath,et al.  Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. , 1996, Journal of immunology.

[29]  R. Karr,et al.  Mice deficient in IL-1beta manifest impaired contact hypersensitivity to trinitrochlorobenzone , 1996, The Journal of experimental medicine.

[30]  David D. Chaplin,et al.  Role of Lymphotoxin and the Type I TNF Receptor in the Formation of Germinal Centers , 1996, Science.

[31]  F. Berenbaum,et al.  Synergistic Effect of Interleukin-1β and Tumor Necrosis Factor α on PGE2Production by Articular Chondrocytes Does Not Involve PLA2Stimulation , 1996 .

[32]  D. Dewitt,et al.  Prostaglandin endoperoxide H synthases-1 and -2. , 1996, Advances in immunology.

[33]  R. Karr,et al.  Mice Deficient in ILI ~ Manifest Impaired Contact Hypersensitivity to Trinitrochlorobenzene , 2003 .

[34]  Hyung-Suk Kim,et al.  Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration , 1995, Cell.

[35]  R. Langenbach,et al.  Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse , 1995, Cell.

[36]  M. Kondo,et al.  Expression of cyclooxygenase-1 and -2 in human colorectal cancer. , 1995, Cancer research.

[37]  K. Chadee,et al.  Proinflammatory cytokines regulate cyclooxygenase-2 mRNA expression in human macrophages. , 1995, Biochemical and biophysical research communications.

[38]  Y. Shibata.  Prostaglandin E2 release triggered by phagocytosis of latex particles. A distinct association with prostaglandin synthase isozymes in bone marrow macrophages. , 1995, Journal of immunology.

[39]  L. Aarden,et al.  Prostaglandin-E2 is a potent inhibitor of human interleukin 12 production , 1995, The Journal of experimental medicine.

[40]  H. Jacobson,et al.  Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. , 1994, The Journal of clinical investigation.

[41]  R. Coffey,et al.  Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. , 1994, Gastroenterology.

[42]  E. Stylianou,et al.  Human peritoneal mesothelial cell prostaglandin synthesis: induction of cyclooxygenase mRNA by peritoneal macrophage-derived cytokines. , 1994, Kidney international.

[43]  S. Higuchi,et al.  NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro. , 1994, Prostaglandins.

[44]  R. Zinkernagel,et al.  Immune response in mice that lack the interferon-gamma receptor. , 1993, Science.

[45]  K. Deschryver,et al.  Treatment with 16,16'-dimethyl prostaglandin E2 before and after induction of colitis with trinitrobenzenesulfonic acid in rats decreases inflammation. , 1989, Gastroenterology.

[46]  J. Spencer,et al.  Evidence that activated mucosal T cells play a role in the pathogenesis of enteropathy in human small intestine , 1988, The Journal of experimental medicine.

[47]  E. Unanue,et al.  Prostaglandins modulate macrophage Ia expression , 1982, Nature.