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INFLAMMATION AND IMMUNOPHARMACOLOGY

Cyclooxygenase-2 Inhibitor SC-236 [4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1-pyrazol-1-l] Benzenesulfonamide] Suppresses Nuclear Factor-B Activation and Phosphorylation of p38 Mitogen-Activated Protein Kinase, Extracellular Signal-Regulated Kinase, and c-Jun N-Terminal Kinase in Human Mast Cell Line Cells

College of Oriental Medicine, Kyung Hee University, Dongdaemun-Gu, Seoul, Republic of Korea (S.-J.K., H.-J.J., I.-Y.C., H.-M.K.); Division of Biological Sciences, College of Natural Science, Chonbuk National University, Jeonju, Jeonbuk, Republic of Korea (S.-J.K., K.-M.L.); and Department of Microbiology and Immunology (R.-K.P.) and College of Pharmacy (H.-J.J., I.-Y.C., S.-H.H.), VestibuloCochlear Research Center of Wonkwang University, Iksan, Jeonbuk, Republic of Korea

SC-236 [4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1-pyrazol-1-l] benzenesulfonamide; C₁₆H₁₁ClF₃N₃O₂S] 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 was to elucidate whether and how SC-236 modulates the inflammatory reaction in a stimulated human mast cell (HMC) line, HMC-1. SC-236 inhibited the expression of tumor necrosis factor-, interleukin (IL)-6, IL-8, vascular endothelial growth factor, COX-2, inducible nitric-oxide synthase, and hypoxia-inducible factor-1 in phorbol 12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated HMC-1. SC-236 suppressed nuclear factor (NF)-B activation induced by PMACI, leading to suppression of IB- phosphorylation and degradation. SC-236 also suppressed strong induction of NF-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.

Address correspondence to: Dr. Hyung-Min Kim, Department of Pharmacology, College of Oriental Medicine, Kyung Hee University, 1 Hoegi-Dong, Dongdaemun-Gu, Seoul, 130-701, Republic of Korea. E-mail: hmkim{at}khu.ac.kr