title: cAMP/PKA enhances interleukin-1β-induced interleukin-6 synthesis through STAT3 in glial cells.
abstract: We previously reported that interleukin (IL)-1β induces IL-6 synthesis via activation of the IκB/NFκB pathway, p38 mitogen-activated protein (MAP) kinase, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and signal transducer and activator of transcription (STAT)3, but not p44/p42 MAP kinase in rat glioma cell line, C6 cells and that cAMP enhances the IL-6 synthesis. However, the details behind enhancement of IL-1β-induced IL-6 synthesis by cAMP remain to be elucidated. In the present study, we investigated the exact mechanism of cAMP underlying the amplification of IL-1β-induced IL-6 synthesis in C6 cells. 8-Bromo cAMP significantly enhanced IL-1β-induced STAT3 phosphorylation without affecting phosphorylation of IκB, p38 MAP kinase or SAPK/JNK. In addition, we found that forskolin, a direct activator of adenylyl cyclase, significantly enhanced IL-1β-induced STAT3 phosphorylation. Janus family of tyrosine kinase (JAK) inhibitor I markedly suppressed the amplification by 8-bromo cAMP of IL-1β-induced IL-6 release. IL-1β induced JAK2 phosphorylation, and FLLL32, a specific JAK2 inhibitor, significantly reduced IL-1β-stimulated IL-6 release. 4-Cyano-3-methylisoquinoline, an inhibitor of protein kinase A (PKA), significantly attenuated the enhancing effect of 8-bromo cAMP on IL-1β-induced STAT3 phosphorylation. 8-Bromo cAMP markedly induced JAK2 phosphorylation. PKA siRNA transfection reduced enhancement of IL-1β-induced IL-6 release by 8-bromo cAMP. In conclusion, our results strongly suggest that the adenylyl cyclase/cAMP/PKA pathway upregulates IL-1β-induced IL-6 synthesis through enhancement of the JAK2/STAT3 pathway in C6 glioma cells.
authors.affiliation: Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan. Electronic address: kumiko-t@m2.gyao.ne.jp.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Tanabe
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan. Electronic address: okozawa@gifu-u.ac.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
authors.affiliation: Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan. Electronic address: iida@gifu-u.ac.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Iida
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005910:Glioma / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism*; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015124:8-Bromo Cyclic Adenosine Monophosphate; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D017868:Cyclic AMP-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Cytokine; Interleukin-1β; Interleukin-6; JAK2; STAT3; cAMP