DIFFERENTIAL CYTOKINE REGULATION OF COMPLEMENT PROTEINS IN HUMAN GLOMERULAR EPITHELIAL-CELLS

We have previously shown in inbred strains of mice which naturally dev elop systemic lupus erythematosus that kidney C3, C2, C4 and factor B gene expression increases coincidently with the occurrence of glomerul onephritis, suggesting that local tissue complement gene expression co uld contribute to the pathogenesis of immune complex injury. In this s tudy, we investigated the synthesis of complement proteins in glomerul ar epithelial cells (GECs) and its regulation. Using biosynthetic labe lling, immunoprecipitation and sodium dodecyl sulfate-poly acrylamide gel electrophoresis, we demonstrated that GECs synthesized C1r, C1s, C 1 inhibitor, C3, C2 and factor B. Interferon-gamma induced increases i n the synthesis of all these proteins. Both factor B and C3 proteins w ere increased following addition of either IL-1 beta, IL-6 or TNF-alph a to GEC cultures; however, these cytokines did not increase either C2 , C1r, C1s or C1-inhibitor biosynthesis. Lipopolysaccharide affected t he biosynthesis of these proteins in a similar way. A semiquantitative analysis of the mRNA expression of some of these proteins by reverse- transcriptase polymerase chain reaction showed that these cytokine eff ects were pretranslational as there was enhancement of factor B mRNA e xpression by IL-1, TNF-alpha, IFN-gamma, IL-6 and endotoxin, but only IFN-gamma enhanced C1-inhibitor and C4 mRNA expression. These results may be of significance in the immunopathogenesis of glomerulonephritis , where it is likely that local complement production in GECs is indep endently regulated by cytokines, derived from resident glomerular mesa ngial cells or infiltrating monocyte/macrophages and T cells.