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

J Pharmacol Exp Ther. 2005 Jul;314(1):27-34. doi: 10.1124/jpet.104.082792. Epub 2005 Mar 22.

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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Blotting, Western
  • Calcimycin / pharmacology
  • Cell Line
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology*
  • Cytokines / biosynthesis
  • Dual Specificity Phosphatase 1
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Genes, Reporter
  • Humans
  • Immunohistochemistry
  • Ionophores / pharmacology
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Luciferases / genetics
  • Mast Cells / drug effects
  • Mast Cells / enzymology*
  • Membrane Proteins
  • Microscopy, Confocal
  • NF-kappa B / antagonists & inhibitors*
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Protein Phosphatase 1
  • Protein Tyrosine Phosphatases / metabolism
  • Pyrazoles / pharmacology*
  • RNA / biosynthesis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stimulation, Chemical
  • Sulfonamides / pharmacology*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tetrazolium Salts
  • Thiazoles
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*

Substances

  • 4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Cytokines
  • Ionophores
  • Membrane Proteins
  • NF-kappa B
  • Pyrazoles
  • Sulfonamides
  • Tetrazolium Salts
  • Thiazoles
  • Calcimycin
  • RNA
  • Luciferases
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Protein Phosphatase 1
  • DUSP1 protein, human
  • Dual Specificity Phosphatase 1
  • Protein Tyrosine Phosphatases
  • thiazolyl blue
  • Tetradecanoylphorbol Acetate