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

A mutant Escherichia coli lipopolysaccharide (LPS) lacking myristoyl fatty acid markedly stimulates the activity of manganese superoxide dismutase (Mn SOD) without inducing tumor necrosis factor alpha (TNF alpha) production by human monocytes (Tian et al., 1998, Am J Physiol 275:C740.), suggesting th at induction of MnSOD and TNF alpha by LPS are regulated through different signal transduction pathways. The protein tyrosine kinase (PTK)/mitogen-act ivated protein kinase (MAPK) pathway plays an important role in the LPS-ind uced TNF alpha production. In the current study, we determined the effects of PTK inhibitors, genistein and herbimycin A, on the induction of MnSOD an d TNF alpha in human monocytes. Genistein (10 mu g/ml) and herbimycin A (1 mu g/ml) markedly inhibited LPS-induced protein tyrosine phosphorylation, p hosphorylation and nuclear translocation of MAPK (p42 ERK, extracellular si gnal-regulated kinase), and increases in the steady state level of TNF alph a mRNA as well as TNF alpha production. In contrast, at similar concentrati ons, genistein and herbimycin A had no effect on the LPS-induced activation of nuclear factor kappa B (NF kappa B) and induction of MnSOD (mRNA and en zyme activity) in human monocytes. In addition, inhibition of NF kappa B ac tivation by gliotoxin and pyrrodiline dithiocarbamate, inhibited LPS induct ion of TNF alpha and MnSOD mRNAs. These results suggest that (1) while PTK and MAPK are essential for the production of TNF alpha, they are not necess ary for the induction of MnSOD by LPS, and (2) while activation of NF kappa B alone is insufficient for the induction of TNF alpha mRNA by LPS, it is necessary for the induction of TNF alpha as well as MnSOD mRNAs. Published 2000 Wiley-Liss, Inc.