Cyclooxygenase-2 inhibitor SC-236 [4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1-pyrazol-1-l] benzenesulfonamide] suppresses nuclear factor-kappaB 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.
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-alpha, interleukin (IL)-6, IL-8, vascular endothelial growth factor, COX-2, inducible nitric-oxide synthase, and hypoxia-inducible factor-1alpha in phorbol 12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated HMC-1. SC-236 suppressed nuclear factor (NF)-kappaB activation induced by PMACI, leading to suppression of IkappaB-alpha phosphorylation and degradation. SC-236 also suppressed strong induction of NF-kappaB 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.
Kim
Su-Jin
SJ
College of Oriental Medicine, Kyung Hee University, Dongdaemun-Gu, Seoul, Republic of Korea.
Jeong
Hyun-Ja
HJ
Choi
In-Young
IY
Lee
Kang-Min
KM
Park
Rae-Kil
RK
Hong
Seung-Heon
SH
Kim
Hyung-Min
HM
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015153:Blotting, Western; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D007476:Ionophores / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008156:Luciferases / Q000235:genetics; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology*; D008565:Membrane Proteins; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013268:Stimulation, Chemical; D013449:Sulfonamides / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013778:Tetrazolium Salts; D013844:Thiazoles; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D000096926:Benzenesulfonamides
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000001:Calcimycin; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D054638:Dual Specificity Phosphatase 1; D048049:Extracellular Signal-Regulated MAP Kinases; D007476:Ionophores; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases; D008565:Membrane Proteins; D016328:NF-kappa B; D011451:Prostaglandin-Endoperoxide Synthases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D011720:Pyrazoles; D012313:RNA; D013449:Sulfonamides; D013755:Tetradecanoylphorbol Acetate; D013778:Tetrazolium Salts; D013844:Thiazoles; D048051:p38 Mitogen-Activated Protein Kinases; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C496540:PTGS2 protein, human; C517019:DUSP1 protein, human; C022616:thiazolyl blue