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

Motility disorders are frequently observed in intestinal inflammation. We previously reported that in vitro treatment of intestinal smooth muscle tissue with IL-1β 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-α and IL-1β were observed to directly inhibit CPI-17 expression and contraction in cultured rat intestinal tissue. Moreover, both TNF-α and IL-1β inhibited CPI-17 expression and contraction of smooth muscle tissue isolated from wild-type and IL-1α/β double-knockout mice. However, IL-1β treatment failed to inhibit CPI-17 expression and contraction in TNF-α knockout mice. In β-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-α plays a central role in this process. Downregulation of CPI-17 may play a role in motility impairments in inflammation.

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Ca2+ signaling in fowl aortic smooth muscle increases during maturation but is impaired in neointimal plaques.

Journal of Experimental Biology ◽

10.1242/jeb.201.11.1695 ◽

1998 ◽

Vol 201 (11) ◽

pp. 1695-1705 ◽

Cited By ~ 1

Author(s):

Z L Qin ◽

H Nishimura

Keyword(s):

Smooth Muscle ◽

Arterial Pressure ◽

Muscle Tissue ◽

Sexual Maturation ◽

Bird Species ◽

Bay K 8644 ◽

Dependent Manner ◽

Smooth Muscle Tissue ◽

Aortic Smooth Muscle ◽

Dose Dependent

Many bird species show the spontaneous development of high arterial pressure and vascular lesions in the aorta and other large arteries. In chickens, arterial pressure tends to increase with age/maturation (particularly in males), and subendothelial hyperplasia (neointima) in the abdominal aorta is often seen prior to sexual maturation. The mechanisms involved, however, are not known. Our aim, therefore, was to determine (1) whether cytosolic Ca2+ signaling (CCS) responses to vasoactive substances in fowl aortic smooth muscle differ among chickens at different maturation stages and (2) whether CCS responses to Ca2+ channel agonists in neointimal plaques differ from those in normal aortic smooth muscle. K+ increased CCS in a dose-dependent manner in isolated and superfused abdominal aortic smooth muscle tissue from chicks (5-9 weeks old), pullets (11-18 weeks old) and adult hens (20 weeks and older); CCS responses increased as chickens matured. The addition of Bay K 8644 (10(-6)mol l-1) to Ringer's solution containing 50 mmol l-1 K+ further increased CCS, and this response was reduced to half by nifedipine (10(-6)mol l-1). Norepinephrine did not alter CCS in chicks, whereas marked dose-dependent increases in CCS were noted in pullets. In contrast to the CCS responses to K+, the norepinephrine-induced CCS responses became smaller in adult hens. Isolated neointimal plaques showed only slight increases in CCS in response to 50 mmol l-1 K+ plus Bay K 8644, whereas clear responses were noted in aortic smooth muscle tissue underlying the plaques. These results suggest (1) that CCS responses to Ca2+ channel agonists increased with sexual maturation in fowl, but (2) that CCS responses to norepinephrine were low in mature hens and to K+ plus Bay K 8644 were low in spontaneously developed neointima, suggesting that phenotypic modulation of Ca2+ channel/norepinephrine receptors may have occurred during maturation/aging and in neointima.

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IL-1β inhibits intestinal smooth muscle proliferation in an organ culture system: involvement of COX-2 and iNOS induction in muscularis resident macrophages

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00487.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. G1315-G1322 ◽

Cited By ~ 17

Author(s):

Takashi Ohama ◽

Masatoshi Hori ◽

Eiichi Momotani ◽

Margaret Elorza ◽

William T. Gerthoffer ◽

...

Keyword(s):

Smooth Muscle ◽

Organ Culture ◽

Smooth Muscle Cells ◽

Muscle Tissue ◽

Culture System ◽

Intestinal Inflammation ◽

Muscle Cells ◽

No Synthase ◽

Smooth Muscle Tissue ◽

Organ Culture System

Intestinal inflammation causes hyperplasia of smooth muscle that leads to thickening of the smooth muscle layer, resulting in dysmotility. IL-1β is a proinflammatory cytokine that plays a central role in intestinal inflammation. In this study, to evaluate the effect of IL-1β on proliferation of ileal smooth muscle cells in vivo, we utilized an organ culture system. When rat ileal smooth muscle tissue was cultured under serum-free conditions for 3 days, most smooth muscle cells maintained their arrangement and kept their contractile phenotype. When 10% FBS was added, an increased number of smooth muscle cells per unit area was observed. Moreover, immunohistochemical staining for PCNA demonstrated that FBS induced proliferation of smooth muscle cells. IL-1β inhibited the proliferative effect of FBS. Furthermore, IL-1β upregulated inducible nitric oxide (NO) synthase and cyclooxygenase-2 mRNA and protein and thus stimulated NO and PGE2productions. Moreover, exogenously applied NO and PGE2inhibited the increase of bromodeoxyuridine-positive cells stimulated with FBS. Immunostaining revealed that the majority of cyclooxygenase-2 and inducible NO synthase was located in the dense network of macrophages resident in the muscularis, which were immunoreactive to ED2. Based on these findings, IL-1β acts as an anti-proliferative mediator, which acts indirectly through the production of PGE2and NO from resident macrophage within ileal smooth muscle tissue.

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