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NEUROREGULATION AND MOTILITY
and causes motility disorders1Department 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-
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