title: Immunomodulatory cytokines suppress epithelial nitric oxide production in inflammatory bowel disease by acting on mononuclear cells.
abstract: Inducible nitric oxide synthase (iNOS) activity in colonic epithelial HT-29 cells is modulated by the T-cell-derived cytokines IL-4 and IL-13, but is not affected by IL-10 despite its effect in models of colitis. We studied the effects of these cytokines on nitric oxide (NO) production by colonic tissue. IL-10 and IL-4 but not IL-13 suppressed the NO production and iNOS expression by inflamed tissue and cytokine-stimulated noninflamed tissue from patients with ulcerative colitis, whereas the three cytokines suppressed NO production in cytokine-stimulated biopsies from controls. To examine why colonic biopsies and HT-29 cells respond differently to immunomodulatory cytokines, a coculture of mixed mononuclear monocytes (MMC) and HT-29 cells was studied. Treatment of HT-29 cells with conditioned medium from IFN-gamma/LPS-stimulated MMC produced significant amounts of NO, which suggested the presence of an MMC-derived soluble factor modifying epithelial NO production. Pretreatment of IFN-gamma/LPS-stimulated MMC with IL-10 and IL-4 but not IL-13 suppressed NO production by HT-29 cells. Interestingly, pretreatment of HT-29 cells with IL-1 receptor antagonist suppressed the IFN-gamma/LPS-stimulated MMC-induced NO production. These results suggest that immunomodulatory cytokines might exert an inhibitory effect on NO up-regulation by colonic epithelium via the inhibition of MMC-derived soluble mediators, such as IL-1.
authors.affiliation: Department of Pharmacology, University of Bath, Bath BA2 7AY, UK.
authors.forename: John D
authors.initials: JD
authors.lastname: Linehan
authors.forename: George
authors.initials: G
authors.lastname: Kolios
authors.forename: Vassilis
authors.initials: V
authors.lastname: Valatas
authors.forename: Duncan A F
authors.initials: DA
authors.lastname: Robertson
authors.forename: John
authors.initials: J
authors.lastname: Westwick
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018920:Coculture Techniques; D003093:Colitis, Ulcerative / Q000276:immunology; D003106:Colon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology; D005260:Female; D019073:HT29 Cells; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D016753:Interleukin-10 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D016753:Interleukin-10; D015847:Interleukin-4; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II