Intracellular signaling mechanisms of interleukin-1beta in synovial fibroblasts |
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Authors: | Kolomytkin, Oleg V. Marino, Andrew A. Sadasivan, Kalia K. Wolf, Robert E. Albright, James A. |
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Abstract: | The possibility that membrane depolarization of synovialfibroblasts caused by interleukin-1 (IL-1) was mediated byprotein kinase C (PKC) and Ca2+influx was studied using inhibitor and activator analysis. The effectof IL-1 was blocked by bisindolylmaleimide I, an inhibitor of PKC,and by the Ca2+ channel blockersnifedipine and verapamil. In other experiments, PKC was activated usingphorbol 12-myristate 13-acetate, andCa2+ influx was increased by meansof a Ca2+ ionophore. Simultaneousapplication of phorbol ester andCa2+ ionophore in the absence ofIL-1 mimicked the depolarization caused by IL-1. The results wereconsistent with the hypothesis that, under the conditions studied,activation of PKC and Ca2+ influxare necessary and sufficient processes in the transduction of IL-1by synovial cells leading to membrane depolarization. Theessential role of protein phosphorylation andCa2+ influx in the earlyelectrophysiological response of synovial fibroblasts to IL-1 wastherefore established. The role of IL-1-induced depolarization inregulating protein expression by the cells remains to be determined,but the results reported here, taken together with observations thatprotein phosphorylation and Ca2+influx also mediate the effect of IL-1 on protease production (1, 2), suggest that electrophysiological changes are actually part of thepathway for expression of proteases in response to IL-1. |
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