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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-

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