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1 Department of Pharmacology, School of Pharmacy, Hoshi University, Shinagewa-ku, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: chiba{at}hoshi.ac.jp.
Bronchial asthma is characterized by chronic inflammation of airway tissues and nonspecific airway hyperresponsiveness (AHR), but the underlying mechanisms of AHR have yet to be elucidated. Recently, tumor necrosis factor-alpha (TNF-alpha) has been identified as a proinflammatory cytokine that might be important in the hyperresponsiveness of airway tissue. Here we investigated the effects of SB203580 (p38 MAPK inhibitor), U0126 (inhibitor of p42/44 MAPK activation) and cycloheximide (inhibitor of protein synthesis) on TNF-alpha-augmented acetylcholine (ACh)-induced bronchial smooth muscle contraction. Furthermore, we investigated the phosphorylation of p42/44 MAPK and upregulation of RhoA protein by TNF-alpha. Treatment of rat bronchial smooth muscles with TNF-alpha (300 and 1000 ng/mL for 24 hr) significantly shifted upward the concentration-response curve to ACh, but not to high K+, as compared to those of control tissues. The effect of TNF-alpha was completely blocked by pretreatment with U0126 or cycloheximide, but not with SB203580. In immunoblotting, p42/44 MAPK was phosphorylated and RhoA protein was increased in bronchial tissue by TNF-alpha. Furthermore, the TNF-alpha-induced upregulation of RhoA protein was abolished by U0126 pretreatment. In conclusion, we suggest that TNF-alpha might be one of the important mediators that are involved in the pathogenesis of augmented bronchial smooth muscle contractility at AHR. We for the first time demonstrated that the augmentation of ACh-induced contractile response evoked by TNF-alpha was mediated by protein synthesis such as RhoA through activation of p42/44 but not of p38 MAPK, in rat bronchial smooth muscle.
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