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 lipopolysaccharide (LPS) are mediated by protein kinase C (PKC), and we have recently demonstrated that a major PKC substrate, MARCKS-related protein (MRP), is selectively induced by LPS in murine microglia. In microglia from LPS-nonresponsive (C3H/HeJ) mice, induction of MRP and secretion of CSF-1 required much higher LPS concentrations (≥100 ng/ml) than in normal (C3H/OuJ) microglia (≤10 ng/ml). By contrast, TNFα production was not significantly increased in C3H/HeJ microgilia even at 1 μg LPS/ml. Microglia expressed PKC isoforms α, β, δ, and ζ (but not γ and ε); PKC isoform levels were similar in both normal and C3H/HeJ microglia and no significant change in response to LPS was noted. Our results indicate that LPS alters PKC substrate (rather than kinase) expression, and that the Lps(d) mutation in C3H/HeJ mice differentially affects regulation of several gene products implicated in microglial function.