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This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/G1429    most recent 00315.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Ohama, T. Articles by Ozaki, H. Search for Related Content PubMed PubMed Citation Articles by Ohama, T. Articles by Ozaki, H.

NEUROREGULATION AND MOTILITY

Intestinal inflammation downregulates smooth muscle CPI-17 through induction of TNF- and causes motility disorders

¹Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo; ²Paratuberculosis and Inflammatory Bowel Disease Research Team, National Institute of Animal Health, Tsukuba; ³Center for Experimental Medicine, Institute of Medical Science, The University of Tokyo, Tokyo; and ⁴Department of Molecular Physiology and Medical Bioregulation, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan

Submitted 18 July 2006 ; accepted in final form 26 January 2007

Motility disorders are frequently observed in intestinal inflammation. We previously reported that in vitro treatment of intestinal smooth muscle tissue with IL-1 decreases the expression of CPI-17, an endogenous inhibitory protein of smooth muscle serine/threonine protein phosphatase, thereby inhibiting contraction. The present study was performed to examine the pathophysiological importance of CPI-17 expression in the motility disorders by using an in vivo model of intestinal inflammation and to define the regulatory mechanism of CPI-17 expression by proinflammatory cytokines. After the induction of acute ileitis with 2,4,6,-trinitrobenzensulfonic acid, CPI-17 expression declined in a time-dependent manner. This decrease in CPI-17 expression was parallel with the reduction of cholinergic agonist-induced contraction of smooth muscle strips and sensitivity of permeabilized smooth muscle fibers to Ca²⁺. Among the various proinflammatory cytokines tested, TNF- and IL-1 were observed to directly inhibit CPI-17 expression and contraction in cultured rat intestinal tissue. Moreover, both TNF- and IL-1 inhibited CPI-17 expression and contraction of smooth muscle tissue isolated from wild-type and IL-1/ double-knockout mice. However, IL-1 treatment failed to inhibit CPI-17 expression and contraction in TNF- knockout mice. In -escin-permeabilized ileal tissues, pretreatment with anti-phosphorylated CPI-17 antibody inhibited the carbachol-induced Ca²⁺ sensitization in the presence of GTP. These findings suggest that CPI-17 was downregulated during intestinal inflammation and that TNF- plays a central role in this process. Downregulation of CPI-17 may play a role in motility impairments in inflammation.

smooth muscle contraction; tumor necrosis factor-