Role of PKC isoforms in the FcγR-mediated inhibition of LPS-stimulated IL-12 secretion by macrophages

Abstract

Ligation of Fc receptors for immunoglobulin G (FcgammaRs) inhibits lipopolysaccharide (LPS)-stimulated secretion of interleukin (IL)-12 by macrophages. FcgammaR activation of protein kinase C (PKC) contributes to several functions of this receptor including phagocytosis, activation of the reduced nicotinamide adenine dinucleotide phosphate oxidase, and secretion of certain cytokines. Therefore, we tested the hypothesis that PKC mediates the FcgammaR inhibition of IL-12 secretion by macrophages. In murine macrophages, FcgammaR ligation augmented LPS-stimulated activation of PKC-alpha and PKC-delta but reduced IL-12p40 secretion. Similarly, activation of PKC with phorbol 12-myristate 13-acetate (PMA) depressed LPS-stimulated IL-12p40 secretion, and depletion of PKC augmented LPS-stimulated IL-12p40 secretion. Antisense down-regulation of PKC-delta increased LPS-stimulated IL-12p40 secretion and fully prevented the effects of FcgammaR ligation or PMA on IL-12p40 secretion. In contrast, down-regulation of PKC-epsilon blocked LPS-stimulated secretion of IL-12p40. Down-regulation of PKC-alpha had no effect on LPS-stimulated IL-12p40 secretion. The results suggest a negative role for PKC-delta and a positive role for PKC-epsilon in the regulation of LPS-stimulated IL-12p40 secretion.