Differential induction of TNF-alpha and MnSOD by endotoxin - Role of reactive oxygen species and NADPH oxidase

Endotoxin (lipopolysaccharide [LPS]) is known to induce the production of t umor necrosis factor (TNF)-alpha and the induction of manganese superoxide dismutase (MnSOD). We have recently demonstrated that induction of TNF-alph a and MnSOD by LPS is mediated through different signal transduction pathwa ys. In the current study, we investigated the role of reactive oxygen speci es (ROS) in the induction of TNF-alpha and MnSOD messenger RNAs (mRNAs) in human monocytes. Hypoxia (1% O-2) inhibited the production of superoxide (O -2(-)) and the induction of MnSOD, but not TNF-alpha, mRNA. Diphenylene iod onium (DPI), a potent inhibitor of the reduced nicotinamide adenine dinucle otide phosphate (NADPH) oxidase, had no effect on LPS induction of MnSOD mR NA, whereas it markedly inhibited LPS-induced O-2(-) production. Neither hy poxia nor DPI had any effect on LPS activation of nuclear factor (NF)-kappa B. These results suggest that (1) ROS is important in the induction of MnSO D, but not TNF-alpha, mRNA by LPS, (2) ROS from sources other than NADPH ox idase is involved in LPS induction of MnSOD mRNA, and (3) ROS-mediated LPS induction of MnSOD mRNA is independent of NF-kappaB activation.