title: Intestinal inflammation downregulates smooth muscle CPI-17 through induction of TNF-alpha and causes motility disorders.
abstract: Motility disorders are frequently observed in intestinal inflammation. We previously reported that in vitro treatment of intestinal smooth muscle tissue with IL-1beta 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 Ca(2+). Among the various proinflammatory cytokines tested, TNF-alpha and IL-1beta were observed to directly inhibit CPI-17 expression and contraction in cultured rat intestinal tissue. Moreover, both TNF-alpha and IL-1beta inhibited CPI-17 expression and contraction of smooth muscle tissue isolated from wild-type and IL-1alpha/beta double-knockout mice. However, IL-1beta treatment failed to inhibit CPI-17 expression and contraction in TNF-alpha knockout mice. In beta-escin-permeabilized ileal tissues, pretreatment with anti-phosphorylated CPI-17 antibody inhibited the carbachol-induced Ca(2+) sensitization in the presence of GTP. These findings suggest that CPI-17 was downregulated during intestinal inflammation and that TNF-alpha plays a central role in this process. Downregulation of CPI-17 may play a role in motility impairments in inflammation.
authors.affiliation: Dept. of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The Univ. of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohama
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hori
authors.forename: Eiichi
authors.initials: E
authors.lastname: Momotani
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Fengling
authors.initials: F
authors.lastname: Guo
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kishi
authors.forename: Sei
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozaki
mesh_terms: D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004195:Disease Models, Animal; D015536:Down-Regulation; D004928:Escin / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000502:physiology*; D007079:Ileitis / Q000139:chemically induced / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000494:pharmacology; D007410:Intestinal Diseases / Q000209:etiology* / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000502:physiology*; D009130:Muscle, Smooth / Q000503:physiopathology*; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000502:physiology*; D051381:Rats; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; C491520:Ppp1r14a protein, mouse; C491519:Ppp1r14a protein, rat; D014409:Tumor Necrosis Factor-alpha; D004928:Escin; D014302:Trinitrobenzenesulfonic Acid; D002217:Carbachol