Abstract
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-α, interleukin (IL)-6, IL-8, vascular endothelial growth factor, COX-2, inducible nitric-oxide synthase, and hypoxia-inducible factor-1α in phorbol 12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated HMC-1. SC-236 suppressed nuclear factor (NF)-κB activation induced by PMACI, leading to suppression of IκB-α phosphorylation and degradation. SC-236 also suppressed strong induction of NF-κB 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.
Footnotes
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This research was supported by the VestibuloCochlear Research Center of Wonkwang University (Grant R13-2002-055-01003-0).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.104.082792.
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ABBREVIATIONS: PG, prostaglandin; TNF, tumor necrosis factor; IL, interleukin; VEGF, vascular endothelial growth factor; COX, cyclooxygenase; iNOS, inducible nitric-oxide synthase; HIF, hypoxia-inducible factor; NF, nuclear factor; MAPK, mitogen-activated protein kinase; ERK, extracellular-regulated kinase; JNK, c-Jun N-terminal kinase; AP, activated protein; MKP, MAPK phosphatase; SC-236, 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1-pyrazol-1-l] benzenesulfonamide; PMA, phorbol 12-myristate 13-acetate; PMACI, PMA plus calcium ionophore A23187; HMC-1, human mast cell line; MTT, 3-[4,5-dimetylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide; Ab, antibody; PBC, phosphate-buffered saline; ELISA, enzyme-linked immunosorbent assay; RT, reverse transcription; PCR, polymerase chain reaction; BSA, bovine serum albumin.
- Received December 23, 2004.
- Accepted March 18, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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