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Activated microglia have been suggested to produce a cytotoxic cytokine, tumor necrosis factor α (TNFα), in many pathological brains. Thus, determining the molecular mechanism of this induction and suppression has been the focus of a great deal of research. Using lipopolysaccharide (LPS) as an experimental inducer of TNFα, we investigated the regulatory mechanism by which TNFα is induced or suppressed in microglia. We found that LPS-induced TNFα is suppressed by pretreatment with the p38 mitogen-activated protein kinase (p38MAPK) inhibitor SB203580. Similar suppression was achieved by pretreatment with specific protein kinase C (PKC) inhibitors, Gö6976, myristoylated pseudosubstrate (20–28), and bisindolylmaleimide. These results suggest that PKCα activity as well as p38MAPK activity is associated with TNFα induction in LPS-stimulated microglia. The requirement of PKCα in LPS-dependent TNFα induction was verified in PKCα-downregulated microglia which could be induced by phorbol-12-myristate-13-acetate pretreatment. Simultaneously, PKCα was found to be requisite for the activation of p38MAPK in LPS-stimulated microglia. In addition, the PKCα levels in the LPS-stimulated microglia were observed to decrease in response to the p38MAPK inhibitor, indicating that the PKCα levels are regulated by the p38MAPK activity.We therefore concluded that PKCα and p38MAPK are interactively linked to the signaling cascade inducing TNFα in LPS-stimulated microglia, and that in this cascade, PKCα is requisite for the activation of p38MAPK, leading to the induction of TNFα.