A mutant Escherichia coli lipopolysaccharide (LPS) lacking myristoyl fatty acid markedly stimulates the activity of manganese superoxide dismutase (MnSOD) without inducing tumor necrosis factor ␣ (TNF␣) production by human monocytes (Tian et al., 1998, Am J Physiol 275:C740.), suggesting that induction of MnSOD and TNF␣ 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 TNF␣ production. In the current study, we determined the effects of PTK inhibitors, genistein and herbimycin A, on the induction of MnSOD and TNF␣ in human monocytes. Genistein (10 g/ml) and herbimycin A (1 g/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 TNF␣ mRNA as well as TNF␣ production. In contrast, at similar concentrations, genistein and herbimycin A had no effect on the LPSinduced activation of nuclear factor B (NFB) and induction of MnSOD (mRNA and enzyme activity) in human monocytes. In addition, inhibition of NFB activation by gliotoxin and pyrrodiline dithiocarbamate, inhibited LPS induction of TNF␣ and MnSOD mRNAs. These results suggest that (1) while PTK and MAPK are essential for the production of TNF␣, they are not necessary for the induction of MnSOD by LPS, and (2) while activation of NFB alone is insufficient for the induction of TNF␣ mRNA by LPS, it is necessary for the induction of TNF␣ as well as MnSOD mRNAs.