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First published on June 5, 2006; DOI: 10.1124/mol.106.024919

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Received for publication March 24, 2006.
Revised May 17, 2006.
Accepted for publication June 5, 2006.

Inhibition of pro-inflammatory TNF-{alpha}-induced iNOS by xanthine-based KMUP-1 and KMUP-3 in rat trachea: the involvement of soluble guanylate cyclase and protein kinase G

Bin-Nan Wu 1, Chien-Wen Chen 2, Shu-Fen Liou 2, Jwu-Lai Yeh 3, Hui-Hsuan Chung 3, Ing-Jun Chen 3*

1 College of Medicine, Kaohsiung Medical University 2 Kaohsiung Medical University 3 Graduate Institute of Pharmacology, Kaohsiung Medical University

* Address correspondence to: E-mail: ingjun{at}kmu.edu.tw

Abstract

In the study of anti-proinflammation by KMUP-1 and KMUP-3, exposure of rat tracheal smooth muscle cells (TSMCs) to tissue necrosis factor-{alpha} (TNF-{alpha}), a pro-inflammatory cytokine, increased the expression of inducible nitric oxide synthase (iNOS) and NO production and decreased the expression of soluble guanylate cyclase {alpha}1 (sGC{alpha}1), soluble guanylate cyclase {beta}1 (sGC{beta}1), protein kinase G (PKG) and the release of cGMP in TSMCs. A cell permeable cGMP analog 8-Br-cGMP, xanthine-based KMUP-1 and KMUP-3 and a phosphodiesterase 5 inhibitor zaprinast all inhibited TNF-{alpha}-induced increases of iNOS expression and NO levels and reversed TNF-{alpha}-induced decreases of sGC{alpha}1, sGC{beta}1 and PKG expression. These results imply cGMP enhancers could have anti-proinflammatory potential in TSMCs. TNF-{alpha} also increased PKA expression and cAMP levels, cyclooxygenase-2 (COX-2) expression and activated productions PGE2 and 6-keto-PGF1{alpha}(stable PGI2 metabolite). Dexamethasone and NS-398 (a selective COX-2 inhibitor) attenuated TNF-{alpha}-induced expression of COX-2 and activated productions PGE2 and PGI2. However, KMUP-1 and KMUP-3 did not affect COX-2 activities and not further enhance cAMP levels in the presence of TNF-{alpha}. It is suggested that TNF-{alpha}-induced increases of PKA expression and cAMP levels are mediated by releasing PGE2 and PGI2, the activation products of COX-2. In conclusion, xanthine-based KMUP-1 and KMUP-3 inhibit TNF-{alpha}-induced expression of iNOS in TSMCs, involving sGC/cGMP/PKG expression pathway, but without the involvement of COX-2.


Key words: Prostanoid, Tumor necrosis factor, cAMP, cGMP, Phosphodiesterases, Protein Kinase A, Protein Kinase G, Eicosanoids


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[Abstract] [Full Text] [PDF]


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