Involvement of protein kinase C in IL-1beta-induced expression of cyclooxygenase-2 in human gingival fibroblasts.
Interleukin-1beta (IL-1beta) stimulates expression of the highly inducible enzyme cyclooxygenase-2 (COX-2) via activation of nuclear factor kappaB (NFkappaB), and consequently provokes prostaglandin E(2) (PGE(2)) synthesis, which induces inflammatory responses. In this study, the contribution of protein kinase C (PKC) to IL-1beta-induced PGE(2) synthesis in human gingival fibroblasts was investigated. The PKC activator phorbol 12-myristate 13-acetate (PMA) stimulated PGE(2) release and COX-2 mRNA expression, as shown in human gingival fibroblasts stimulated by IL-1beta. However, PMA showed only a weak effect on the formation of COX-2-NFkappaB DNA-protein complex, whereas IL-1beta had a clearly stimulatory effect. In cells in which PMA-dependent PKC was down-regulated, PMA failed to induce the formation of NFkappaB DNA-protein complex and reduced the release of PMA-induced PGE(2), whereas IL-1beta stimulated the formation of COX-2-NFkappaB DNA-protein complex and PGE(2) release. The atypical PKC (aPKC) inhibitor Gö6983 clearly suppressed the formation of COX-2-NFkappaB DNA-protein complex and PGE(2) release stimulated by IL-1beta but not the inhibitor of conventional PKC (cPKC) and the novel PKC (nPKC) inhibitor Gö6976. These observations suggest that aPKC is involved in IL-1beta-induced PGE(2) synthesis, which is controlled by transcription of the COX-2 gene via the NFkappaB-dependent pathway in human gingival fibroblasts.
Department of Oral Molecular Pharmacology, Nihon University School of Dentistry at Matsudo, Japan. nakao.sumi@nihon-u.ac.jp
Sumi
S
Nakao
Daisuke
D
Inoue
D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D005881:Gingiva / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D007211:Indoles; D053583:Interleukin-1beta / Q000502:physiology*; D008301:Maleimides; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; D002227:Carbazoles; D007211:Indoles; D053583:Interleukin-1beta; D008301:Maleimides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; C081021:Go 6976; D051546:Cyclooxygenase 2; D011493:Protein Kinase C; D015232:Dinoprostone