The role of protein kinase C and calcium in induction of human polymorphonuclear leukocyte IL-1 beta gene expression by GM-CSF

At infection sites, synthesis of interleukin (IL-)1 beta by polymorphonucle ar leukocytes (PMNs) facilitates the recruitment of inflammatory cells and enhances the inflammatory response. We investigated the role of protein kin ase C (PKC) and Ca2+ in the induction of PMN IL,-1 beta gene expression by GM-CSF, The PKC inhibitors chelerythrine and H7 blocked induction of IL-1 b eta mRNA expression in human PMNs, HA1004, an H7 analogue with little activ ity towards PKC, had no inhibitory effect, Similarly, H7 blocked IL-1 beta transcription in nuclear run-on analysis, while HA1004 had little effect. T he intracellular Ca2+ chelator BAPTA/AM inhibited induction of IL-1 beta mR NA accumulation and transcription by GM-CSF, At concentrations similar to t hose used to inhibit IL-1 beta gene expression, H7, chelerythrine, and BAPT A all inhibited substrate phosphorylation by PKC isolated from PMN lysates, Thus, PKC and Ca2+ are potential targets for modulating an important PMN i mmunoregulatory function. (C) 2000 Academic Press.