LIPOPOLYSACCHARIDE INDUCTION OF MARCKS-RELATED PROTEIN AND CYTOKINE SECRETION ARE DIFFERENTIALLY IMPAIRED IN MICROGLIA FROM LPS-NONRESPONSIVE (C3H HEJ) MICE/

Many events involved in activation of microglia and leukocytes by lipo polysaccharide (LPS) are mediated by protein kinase C (PKC), and we ha ve recently demonstrated that a major PKC substrate, MARCKS-related pr otein (MRP), is selectively induced by LPS in murine microglia. In mic roglia from LPS-nonresponsive (C3H/HeJ) mice, induction of MRP and sec retion of CSF-1 required much higher LPS concentrations (greater than or equal to 100 ng/ml) than in normal (C3H/OuJ) microglia (less than o r equal to 10 ng/ml). By contrast, TNF alpha production was not signif icantly increased in C3H/HeJ microglia even at 1 mu g LPS/ml. Microgli a expressed PKC isoforms alpha, beta, delta, and zeta (but not gamma a nd epsilon); PKC isoform levels were similar in both normal and C3H/He J microglia and no significant change in response to LPS was noted. Ou r results indicate that LPS alters PKC substrate (rather than kinase) expression, and that the Lps(d) mutation in C3H/HeJ mice differentiall y affects regulation of several gene products implicated in microglial function.