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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on March 22, 2005; DOI: 10.1124/jpet.104.082792

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*12-O-TETRADECANOYLPHORBOL-13-ACETATE


Received for publication December 23, 2004.
Revised March 17, 2005.
Accepted for publication March 18, 2005.

Cyclooxygenase-2 Inhibitor (SC-236) Suppresses NF-{kappa}B Activation and Phosphorylation of p38 MAPK, ERK, and JNK in HMC-1 Cells

Su-Jin Kim 1, Hyun-Ja Jeong 2, In-Young Choi 2, Kang-Min Lee 3, Rae-Kil Park 4, Seung-Heon Hong 5, Hyung-Min Kim 6*

1 College of Oriental Medicine, Kyung Hee University;College of Natural Science, Chonbuk National Univ 2 College of Oriental Medicine, Kyung Hee University; College of Pharmacy, VCRC of Wonkwang University 3 Division of Biological Science, College of Natural Science, Chonbuk National University 4 Department of Microbiology and Immunology, VestibuloCochlear Research Center of Wonkwang University 5 College of Pharmacy, VestibuloCochlear Research Center of Wonkwang University 6 College of Oriental Medicine, Kyung Hee University

* Address correspondence to: E-mail: hmkim{at}khu.ac.kr

Abstract

SC-236, (4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1- pyrazol-1-l] benzenesulfonamide; C16H11ClF3N3O 2S), is a highly selective cyclooxygenase (COX)-2 inhibitor. However, the exact mechanism that accounts for the anti-inflammatory effect of SC-236 is not completely understood. The aim of the present study is to elucidate whether and how SC-236 modulates the inflammatory reaction in a stimulated human mast cell line, HMC-1. SC-236 inhibited the expression of tumor necrosis factor-{alpha}, interleukin (IL)-6, IL-8, vascular endothelial growth factor, COX-2, inducible nitric oxide synthase, and hypoxia-inducible factor-1{alpha} in phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore A23187 (PMACI)-stimulated HMC-1. SC- 236 suppressed nuclear factor (NF)-{kappa}B activation induced by PMACI, leading to suppression of I{kappa}B-{alpha} phosphorylation and degradation. SC-236 also suppressed strong induction of NF-{kappa}B promoter- mediated luciferase activity. In addition, SC-236 suppressed PMACI -induced phosphorylation of the mitogen- activated protein kinase p38, the extracellular- regulated kinase p44, and the c-Jun N-terminal kinase and induced expression of mitogen-activated protein kinase phosphatase-1. These results provide new insight into the pharmacological actions of SC-236 as a potential molecule for therapy of mast cell-mediated inflammatory diseases.


Key words: COX-2, Cytokines, Hypoxia-inducible factor-1{alpha}, Inducible nitric oxide synthase, Nuclear factor, SC-236




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