Nonparticipation of nuclear factor kappa B (NFκB) in the signaling cascade of c-Jun N-terminal kinase (JNK)- and p38 mitogen-activated protein kinase (p38MAPK)-dependent tumor necrosis factor alpha (TNFα) induction in lipopolysaccharide (LPS)-stimulated microglia

Abstract The molecular mechanism of cytotoxic cytokine tumor necrosis factor α (TNFα) induction in microglia remains to be clarified. We have previously reported that p38 mitogen-activated protein kinase (p38MAPK) is an important signaling molecule for the induction of TNFα in lipopolysaccharide (LPS)-stimulated microglia. Recently, we have shown that c-Jun N-terminal kinase (JNK) is associated with the induction of TNFα. Furthermore, using an NFκB inhibitor (SN50), we discovered that activation of nuclear factor κB (NFκB) may also be linked to TNFα induction. We therefore examined the relationship between NFκB and the two MAPKs (p38MAPK and JNK) in the signaling cascade of TNFα induction in LPS-stimulated microglia. NFκB inhibitor SN50 decreased the induction of TNFα under the suppressed NFκB activation. However, SN50 was found to prevent the activation of MKK3/6-p38MAPK and MKK4-JNK pathways. On the other hand, the other NFκB inhibitor ammonium pyrrolidine dithiocarbamate (APDC) neither prevented the activation of p38MAPK and JNK nor inhibited TNFα induction in LPS-stimulated microglia, although it was confirmed to serve as an NFκB inhibitor. These results suggest that both MKK3/6-p38MAPK and MKK4-JNK pathways are important signaling cascades leading to the induction of TNFα in LPS-stimulated microglia, but that NFκB itself is not required for this induction.