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J. Biol. Chem., Vol. 278, Issue 49, 48794-48804, December 5, 2003

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Chronic Treatment with Interleukin-1 Attenuates Contractions by Decreasing the Activities of CPI-17 and MYPT-1 in Intestinal Smooth Muscle^*

Takashi Ohama, Masatoshi Hori, Koichi Sato, Hiroshi Ozaki, and Hideaki Karaki

From the Department of Veterinary Pharmacology and Radioisotope Center, Graduate School of Agriculture and Life Sciences, the University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan

Interleukin-1 (IL-1) is a proinflammatory cytokine that plays a central role in inflammatory bowel disease (IBD). In order to elucidate the mechanism of motility disorders frequently observed in IBD, we investigated the long term effects of IL-1 on rat ileal smooth muscle contractility by using an organ culture system. When ileal smooth muscle strips were cultured with IL-1 (10 ng/ml), contractions elicited by high K⁺ and carbachol were inhibited in a time-dependent manner. IL-1 more strongly inhibited the carbachol-induced contractions than high K⁺ with decreasing myosin light chain phosphorylation. In the -toxin-permeabilized ileal muscle, carbachol with GTP or guanosine 5'-3-O-(thio)triphosphate increased the Ca²⁺ sensitivity of contractile elements, and this G protein-coupled Ca²⁺ sensitization was significantly reduced in the IL-1-treated ileum. Among the functional proteins involved in the smooth muscle Ca²⁺ sensitization, CPI-17 expression was significantly reduced after the culture with IL-1, whereas the expressions of RhoA, ROCK-I, ROCK-II, MYPT-1, myosin light chain kinase, and myosin phosphatase (PP1) were unchanged. The phosphorylation level of CPI-17 by carbachol was low in accordance with the decrease in CPI-17 expression due to IL-1 treatment. In contrast, constitutively phosphorylated MYPT-1 was also decreased in the IL-1-treated muscles. These results suggest that long term treatment with IL-1 decreases either CPI-17 expression or MYPT-1 phosphorylation, which may result in an increase in myosin phosphatase activity to reduce force generation. Based on these findings, we consider IL-1 to be an important mediator of gastrointestinal motility disorders in IBD, and CPI-17 and MYPT-1 are key molecules in the decreased smooth muscle contractility due to IL-1.

Received for publication, September 12, 2003

^* This work was supported by the Program for the Promotion of Basic Research Activities for Innovative Biosciences, The Yakult Foundation, Morinaga Hoshi-kai, and a Grant-in-aid for Scientific Research from the Japanese Ministry of Education, Culture, and Science. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, the University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan. Tel.: 81-3-5841-5393; Fax: 81-3-58411-8183.

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