Interleukin-1beta-induced cyclooxygenase-2 expression is mediated through activation of p42/44 and p38 MAPKS, and NF-kappaB pathways in canine tracheal smooth muscle cells

Cell Signal. 2002 Nov;14(11):899-911. doi: 10.1016/s0898-6568(02)00037-2.

Abstract

Interleukin-beta (IL-1beta) was found to induce inflammatory responses in the airways, which exerted a potent stimulus for PG synthesis. This study was to determine the mechanisms of IL-1beta-enhanced cyclooxygenase (COX)-2 expression associated with PGE(2) synthesis in tracheal smooth muscle cells (TSMCs). IL-1beta markedly increased COX-2 expression and PGE(2) formation in a time- and concentration-dependent manner in TSMCs. Both COX-2 expression and PGE(2) formation in response to IL-1beta were attenuated by a tyrosine kinase inhibitor, genistein, a phosphatidylcholine-phospholipase C inhibitor, D609, a phosphatidylinositol-phospholipase C inhibitor, U73122, protein kinase C inhibitors, GF109203X and staurosporine, removal of Ca(2+) by addition of BAPTA/AM plus EGTA, and phosphatidylinositol 3-kinase (PI3-K) inhibitors, LY294002 and wortmannin. IL-1beta-induced activation of NF-kappaB correlated with the degradation of IkappaB-alpha in TSMCs. IL-1beta-induced NF-kappaB activation, COX-2 expression, and PGE(2) synthesis were inhibited by the dominant negative mutants of NIK and IKK-alpha, but not by IKK-beta. IL-1beta-induced COX-2 expression and PGE(2) synthesis were completely inhibited by PD98059 (an inhibitor of MEK1/2) and SB203580 (an inhibitor of p38 inhibitor), but these two inhibitors had no effect on IL-1beta-induced NF-kappaB activation, indicating that activation of p42/44 and p38 MAPK and NF-kappaB signalling pathways were independently required for these responses. These findings suggest that the increased expression of COX-2 correlates with the release of PGE(2) from IL-1beta-challenged TSMCs, at least in part, independently mediated through MAPKs and NF-kappaB signalling pathways in canine TSMCs. IL-1beta-mediated responses were modulated by PLC, Ca(2+), PKC, tyrosine kinase, and PI3-K in these cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / enzymology
  • Asthma / physiopathology
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology
  • Cells, Cultured
  • Cyclooxygenase 2
  • Dinoprostone / biosynthesis*
  • Dogs
  • Female
  • I-kappa B Kinase
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Interleukin-1 / metabolism*
  • Interleukin-1 / pharmacology
  • Isoenzymes / metabolism*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Male
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / enzymology*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Pneumonia / enzymology
  • Pneumonia / physiopathology
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Trachea / cytology
  • Trachea / enzymology*
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / metabolism

Substances

  • I-kappa B Proteins
  • Interleukin-1
  • Isoenzymes
  • NF-kappa B
  • Phosphoinositide-3 Kinase Inhibitors
  • NF-KappaB Inhibitor alpha
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase
  • Protein Kinase C
  • Type C Phospholipases
  • Dinoprostone