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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Interleukin 1-Induced Production of H₂O₂ Contributes to Reduced Sigmoid Colonic Circular Smooth Muscle Contractility in Ulcerative Colitis

Departments of Medicine (W.C., K.M.H.) and Surgery (M.D.V., F.M.P., V.E.P.), Rhode Island Hospital and Brown Medical School, Providence, Rhode Island; and Division of Gastroenterology (C.F.), Case Western Reserve University School of Medicine, Cleveland, Ohio

We have shown that neurokinin A-induced contraction of human sigmoid circular muscle (HSCM) is reduced in patients with ulcerative colitis and that interleukin (IL)-1 may play a role in this change. We now examine changes in the signal transduction pathway mediating neurokinin A-induced contraction of HSCM and explore the role of IL-1 and of H₂O₂ in these changes. In Fura 2-AM-loaded ulcerative colitis HSCM cells, neurokinin A- and caffeine-induced peak Ca²⁺ increase and cell shortening were significantly reduced. In normal cells, neurokinin A-induced contraction was decreased by protein kinase C inhibitor chelerythrine and by calmodulin inhibitor CGS9343B [1,3-dihydro-1-[1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]-benzoxazepin-4-yl)methyl]-4-piperidinyl]-2H-benzimidazol-2-one (1:1) maleate]. In ulcerative colitis muscle cells, contraction was inhibited only by chelerythrine but not by CGS9343B. IL-1 treatment of normal HSCM strips and cells reproduced the changes observed in ulcerative colitis. IL-1-induced reduction in caffeine-induced peak Ca²⁺ increase and contraction was reversed by catalase, suggesting a role of H₂O₂. IL-1-induced H₂O₂ production was inhibited by mitogen-activated protein kinase (MAPK) kinase inhibitor PD98059 (2'-amino-3'-methoxyflavone) and by cytosolic phospholipase A2 (cPLA₂) inhibitor AACOCF3 (arachidonyltrifluoromethyl ketone), but neither by p38 MAPK inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole] nor by nuclear factor-B (NF-B) inhibitory peptide NF-B SN50 (H-Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Leu-Leu-Ala-Pro-Val-Gln-Arg-Lys-Arg-Gln-Lys-Leu-Met-Pro-OH). IL-1 significantly increased the phosphorylation of extracellular signal-regulated kinase 1 (ERK1)/ERK2 MAPKs and cPLA₂ and IL-1-induced cPLA₂ phosphorylation was blocked by PD98059. We conclude that Ca²⁺ stores of HSCM cells may be reduced in ulcerative colitis and that the signal transduction pathway of neurokinin A-induced contraction switches from calmodulin- and protein kinase C-dependent in normal cells to protein kinase C-dependent in ulcerative colitis cells. IL-1 reproduces these changes, possibly by production of H₂O₂ via sequential activation of MAPKs (ERK1/ERK2) and cPLA₂.

Address correspondence to: Dr. Victor E. Pricolo, Department of Surgery, Brown Medical School and Rhode Island Hospital, 2 Dudley St., Suite 470, Providence, RI 02905. E-mail: vpricolo{at}usasurg.org

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