Synergistic effects of cAMP-dependent signalling pathways and IL-1 on IL-6 production by H19-7/IGF-IR neuronal cells.
cAMP-dependent signalling cascades regulate a number of CNS functions including brain inflammation processes. In this study, we characterized IL-1-induced IL-6 production in hippocampal cells using H19-7/IGF-IR cells and investigated the effect of changes in intracellular cAMP levels on IL-1 activity. IL-1 potently induced IL-6 mRNA expression with a corresponding increase in IL-6 release, in a time- and dose-dependent manner with a maximal at 24 h and with an EC50 value of 0.11 ng/ml. Cell pre-treatment with the IL-1sR antagonist produced a rightward shift of IL-1 dose-response effect with a corresponding decrease in IL-1 potency. IL-1-induced IL 6 release was attenuated in the presence of the p38 MAPK inhibitor SB203580 but was not significantly affected by the PKA inhibitor KT 5720. Western blotting analysis of phospho-CREB cell content showed a marked increase in CREB activation. Similar results were obtained by pharmacologically increasing cAMP using dibutyryl cyclic adenosine monophosphate (dbcAMP) or the cAMP-specific type-4 phosphodiesterase inhibitor rolipram. Both dbcAMP and rolipram increased IL-6 production to about 50% of IL-1 effect. However, in the presence of IL-1, IL-6 production was further potentiated by either dbcAMP and rolipram, reaching 300% and 500% IL-1-induced levels. These data implicate the role of cAMP-dependent pathways on IL-6 production in neuronal cells and suggest novel synergistic mechanisms of regulation of cytokine production in brain.
Neuropharmacology Research Department, GlaxoSmithKline S.p.A., Psychiatry Center of Excellence for Drug Discovery, Via A. Fleming 4, IT-37135 Verona, Italy.
Anna
A
Bergamaschi
Mauro
M
Corsi
Martine J
MJ
Garnier
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology*; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017472:Receptors, Interleukin-1 / Q000235:genetics; D019947:Receptors, Interleukin-6 / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D017362:Cyclic AMP Response Element-Binding Protein; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D019947:Receptors, Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D003994:Bucladesine; D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020889:Rolipram