Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 48, Pages 41552-41562Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.274449
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Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan [23591187, 20590953]
- University of Yamanashi
- Grants-in-Aid for Scientific Research [21390324, 20590953, 23591187] Funding Source: KAKEN
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Gap junctions (GJs) play an important role in the control of bladder contractile response and in the regulation of various immune inflammatory processes. Here, we investigated the possible interaction between inflammation and GJs in bladder smooth muscle cells (BSMCs). Stimulation of BSMCs with IL1 beta and TNF alpha increased connexin43 (Cx43) expression and function, which was associated with increased phosphorylation of vasodilator-stimulated phosphoprotein. Inhibition of PKA with H89 or down-regulation of CREB with specific siRNAs largely abolished the Cx43-elevating effect. Further analysis revealed that IL1 beta/TNF alpha induced NF kappa B-dependent inducible NO synthase (iNOS) expression. Inhibition of iNOS with G-nitro-L-arginine methyl ester abrogated and an exogenous NO donor mimicked the effect of the cytokines on Cx43. Intraperitoneal injection of LPS into mice also induced bladder Cx43 expression, which was largely blocked by an iNOS inhibitor. Finally, the elevated Cx43 was found to negatively regulate iNOS expression. Dysfunction of GJs with various blockers or down-regulation of Cx43 with siRNA significantly potentiated the expression of iNOS. Fibroblasts from Cx43 knock-out (Cx43(-/-)) mice also displayed a significantly higher response to the cytokine-induced iNOS expression than cells from Cx43 wild-type (Cx43(+/+)) littermates. Collectively, our study revealed a previously unrecognized reciprocal regulation loop between cytokine-induced NO and GJs. Our findings may provide an important molecular mechanism for the symptoms of bladder infection. In addition, it may further our understanding of the roles of GJs in inflammatory diseases.
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