Differential induction of tumor necrosis factor α and manganese superoxide dismutase by endotoxin in human monocytes: Role of protein tyrosine kinase, mitogen-activated protein kinase, and nuclear factor κB

A mutant Escherichia coil lipopolysaccharide (LPS) lacking myristoyl fatty acid markedly stimulates the activity of manganese superoxide dismutase (MnSOD) without inducing tumor necrosis factor α (TNFα) production by human monocytes (Tian et al., 1998, Am J Physiol 275:C740.), suggesting that induction of MnSOD and TNFα by LPS are regulated through different signal transduction pathways. The protein tyrosine kinase (PTK)/mitogen-activated protein kinase (MAPK) pathway plays an important role in the LPS-induced TNFα production. In the current study, we determined the effects of PTK inhibitors, genistein and herbimycin A, on the induction of MnSOD and TNFα in human monocytes. Genistein (10 μg/ml) and herbimycin A (1 μg/ml) markedly inhibited LPS-induced protein tyrosine phosphorylation, phosphorylation and nuclear translocation of MAPK (p42 ERK, extracellular signal-regulated kinase), and increases in the steady state level of TNFα mRNA as well as TNFα production. In contrast, at similar concentrations, genistein and herbimycin A had no effect on the LPS-induced activation of nuclear factor κB (NFκB) and induction of MnSOD (mRNA and enzyme activity) in human monocytes. In addition, inhibition of NFκB activation by gliotoxin and pyrrodiline dithiocarbamate, inhibited LPS induction of TNFα and MnSOD mRNAs. These results suggest that (1) while PTK and MAPK are essential for the production of TNFα, they are not necessary for the induction of MnSOD by LPS, and (2) while activation of NFκB alone is insufficient for the induction of TNFα mRNA by LPS, it is necessary for the induction of TNFα as well as MnSOD mRNAs.