TY - JOUR T1 - Involvement of Protein Kinase C-γ in IL-1β-Induced Cyclooxygenase-2 Expression in Human Pulmonary Epithelial Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 36 LP - 43 VL - 57 IS - 1 AU - Chien-Huang Lin AU - Sheng-Yuan Sheu AU - Horng-Mo Lee AU - Yuan-Soon Ho AU - Wen-Sen Lee AU - Wun-Chang Ko AU - Joen-Rong Sheu Y1 - 2000/01/01 UR - http://molpharm.aspetjournals.org/content/57/1/36.abstract N2 - The signaling pathway of protein kinase C (PKC) is known to play a role in mediating the action of various cytokines. Here we examined the signal transduction pathway of PKC activation and the role of PKC isoforms in interleukin-1β (IL-1β)-mediated cyclooxygenase-2 (COX-2) expression in human pulmonary epithelial cell line (A549). The tyrosine kinase inhibitors (genistein and tyrphostin AG126) and phosphatidylcholine-phospholipase C inhibitor (D-609) prevented IL-1β-induced prostaglandin E2 (PGE2) release and COX-2 expression, whereas U-73122 (a phosphatidylinositol-phospholipase C inhibitor) and propranolol (a phosphatidate phosphohydrolase inhibitor) had no effect. The PKC inhibitors (Go 6976 and Ro 31–8220) and NF-κB inhibitor, pyrrolidine dithiocarbamate, also attenuated IL-1β-induced PGE2release and COX-2 expression. Western blot analysis using PKC isoenzyme-specific antibodies indicated that A549 cells expressed PKC-α, -γ, -ι, -λ, -ζ, and -μ. IL-1β caused the translocation of PKC-γ but not other isoforms from cytosol to the membrane fraction. Moreover, the translocation of PKC-γ was inhibited by genistein or D-609, but not by U-73122. IL-1β caused the translocation of p65 NF-κB from cytosol to the nucleus as well as the degradation of IκB-α in cytosol. Furthermore, the translocation of p65 NF-κB was inhibited by genistein, Go 6976, Ro 31–8220, or pyrrolidine dithiocarbamate. These results indicate that in human pulmonary epithelial cells, IL-1β might activate phosphatidylcholine-phospholipase C through an upstream tyrosine phosphorylation to elicit PKC activation, which in turn initiates NF-κB activation, and finally induces COX-2 expression and PGE2 release. Of the PKC isoforms present in A549 cells, only activation of PKC-γ is involved in regulating IL-1β-induced responses. The American Society for Pharmacology and Experimental Therapeutics ER -