Intestinal inflammation downregulates smooth muscle CPI-17 through induction of TNF-α and causes motility disorders
Intestinal inflammation downregulates smooth muscle CPI-17 through induction of TNF-α and causes motility disorders
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DOI：
10.1152/ajpgi.00315.2006
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发表时间：
2007-05-01
影响因子：
4.5
通讯作者：
Ozaki, Hiroshi
中科院分区：
文献类型：
--
作者：
Ohama, Takashi;Hori, Masatoshi;Ozaki, Hiroshi
肠动力障碍常见于肠道炎症。我们先前报道，在体外用IL-1β处理肠平滑肌组织会减少CPI-17的表达，CPI-17是一种平滑肌丝氨酸/苏氨酸蛋白磷酸酶的内源性抑制蛋白，从而抑制收缩。本研究通过在体肠炎症模型探讨CPI-17表达在肠动力障碍中的病理生理学意义，并探讨促炎症细胞因子对CPI-17表达的调节机制。用2，4，6-三硝基苯磺酸诱导急性回肠炎后，CPI-17的表达呈时间依赖性下降。CPI-17表达的减少与胆碱能激动剂诱导的平滑肌条收缩和通透性平滑肌纤维对钙的敏感性的减少是平行的。在所测试的各种促炎细胞因子中，发现肿瘤坏死因子-α和白介素1-β能直接抑制培养的大鼠肠组织中CPI-17的表达和收缩。此外，TNF-α和IL-1α均抑制野生型和IL-1α/β双基因敲除小鼠分离的平滑肌组织CPI-17的表达和收缩。然而，IL-1β治疗未能抑制肿瘤坏死因子-α基因敲除小鼠的CPI-17的表达和收缩。在β-七叶皂苷通透性回肠组织中，抗磷酸化CPI-17抗体可抑制氨甲酰胆碱在GTP存在下引起的钙敏化。这些发现表明，CPI-17在肠道炎症过程中被下调，而肿瘤坏死因子-α在这一过程中起着核心作用。CPI-17的下调可能在炎症中的运动性损伤中发挥作用。
Motility disorders are frequently observed in intestinal inflammation. We previously reported that in vitro treatment of intestinal smooth muscle tissue with IL-1 beta 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-alpha and IL-1 beta were observed to directly inhibit CPI-17 expression and contraction in cultured rat intestinal tissue. Moreover, both TNF-alpha and IL-1 alpha inhibited CPI-17 expression and contraction of smooth muscle tissue isolated from wild-type and IL-1 alpha/beta double-knockout mice. However, IL-1 beta 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 Ca2+ 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.