Downregulation of CPI-17 contributes to dysfunctional motility in chronic intestinal inflammation model mice and ulcerative colitis patients.
BACKGROUND
Chronic intestinal inflammation is frequently accompanied by motility disorders. We previously reported that proinflammatory cytokines, such as tumor necrosis factor alpha and interleukin (IL)-1beta downregulate CPI-17, an endogenous inhibitor of serine/threonine protein phosphatase in smooth-muscle cells, which results in the inhibition of myosin light chain phosphorylation and contractility. However, its clinical relevance has not been clarified.


METHODS
The present study examined the changes in CPI-17 expression in chronic intestinal inflammation using smooth-muscle tissues from IL-10 knockout mice and from patients with ulcerative colitis (UC).


RESULTS
The IL-10 knockout mice developed spontaneous and chronic colitis accompanied by immune cell infiltration, submucosal fibrosis, and thickening of the muscularis externa. The expression of alpha-smooth muscle actin protein in the smooth-muscle layer did not change, whereas that of CPI-17 protein was decreased by about 40% compared with healthy wild-type controls. Consistent with this observation, smooth-muscle contractile force and myosin light chain phosphorylation induced by a muscarinic agonist were reduced in the knockout mice. Moreover, we observed that CPI-17 protein expression was decreased in smooth-muscle tissues from patients with UC compared with controls.


CONCLUSIONS
CPI-17 downregulation might contribute to the decreased motor function in chronic inflammatory bowel diseases.
Ohama
Takashi
T
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
Hori
Masatoshi
M
Fujisawa
Masahiko
M
Kiyosue
Masaharu
M
Hashimoto
Masaki
M
Ikenoue
Yuka
Y
Jinno
Yoshio
Y
Miwa
Hiroto
H
Matsumoto
Takayuki
T
Murata
Takahisa
T
Ozaki
Hiroshi
H
D000818:Animals; D015153:Blotting, Western; D003093:Colitis, Ulcerative / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003106:Colon / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D005769:Gastrointestinal Motility / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000096:biosynthesis*; D009129:Muscle Tonus / Q000502:physiology; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D010750:Phosphoproteins / Q000096:biosynthesis*
D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C107507:PPP1R14A protein, human; D010750:Phosphoproteins; C491520:Ppp1r14a protein, mouse; D010749:Phosphoprotein Phosphatases