title: Intracellular signaling mechanisms of interleukin-1beta in synovial fibroblasts.
abstract: The possibility that membrane depolarization of synovial fibroblasts caused by interleukin-1beta (IL-1beta) was mediated by protein kinase C (PKC) and Ca2+ influx was studied using inhibitor and activator analysis. The effect of IL-1beta was blocked by bisindolylmaleimide I, an inhibitor of PKC, and by the Ca2+ channel blockers nifedipine and verapamil. In other experiments, PKC was activated using phorbol 12-myristate 13-acetate, and Ca2+ influx was increased by means of a Ca2+ ionophore. Simultaneous application of phorbol ester and Ca2+ ionophore in the absence of IL-1beta mimicked the depolarization caused by IL-1beta. The results were consistent with the hypothesis that, under the conditions studied, activation of PKC and Ca2+ influx are necessary and sufficient processes in the transduction of IL-1beta by synovial cells leading to membrane depolarization. The essential role of protein phosphorylation and Ca2+ influx in the early electrophysiological response of synovial fibroblasts to IL-1beta was therefore established. The role of IL-1beta-induced depolarization in regulating protein expression by the cells remains to be determined, but the results reported here, taken together with observations that protein phosphorylation and Ca2+ influx also mediate the effect of IL-1beta on protease production (1, 2), suggest that electrophysiological changes are actually part of the pathway for expression of proteases in response to IL-1beta.
authors.affiliation: Department of Orthopaedic Surgery, Department of Medicine, Louisiana State University Medical Center, Shreveport, Louisiana 71130-3932, USA.
authors.forename: O V
authors.initials: OV
authors.lastname: Kolomytkin
authors.forename: A A
authors.initials: AA
authors.lastname: Marino
authors.forename: K K
authors.initials: KK
authors.lastname: Sadasivan
authors.forename: R E
authors.initials: RE
authors.lastname: Wolf
authors.forename: J A
authors.initials: JA
authors.lastname: Albright
mesh_terms: D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000502:physiology*; D007425:Intracellular Membranes / Q000502:physiology*; D007476:Ionophores / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology*; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D007211:Indoles; D007375:Interleukin-1; D007476:Ionophores; D008301:Maleimides; D000001:Calcimycin; D014700:Verapamil; D009543:Nifedipine; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate