DIMETHYL-SULFOXIDE MODULATES NF-KAPPA-B AND CYTOKINE ACTIVATION IN LIPOPOLYSACCHARIDE-TREATED MURINE MACROPHAGES

Antioxidants are protective against septic shock in animal models. Rec ently, free radical scavengers have been found to inhibit the activati on of the NF-kappa B protein in a number of cell lines. This transcrip tional regulatory protein binds to the promoters of the proinflammator y cytokines tumor necrosis factor, interleukin-6, and the macrophage i nflammatory proteins. The current work examined lipopolysaccharide-ind uced NF-kappa B activation in the J774 macrophage-like cell line and p rimary peritoneal macrophages from lipopolysaccharide-responsive (C3He B/Fej) and -nonresponsive (C3H/HeJ) murine strains. The DNA-binding ac tivity of the NF-kappa B protein directly correlated with mRNA express ion for the genes encoding the proinflammatory cytokines and the free radical scavenging enzyme, superoxide dismutase. Both the p50 and p65 NF-kappa B subunits were detected on gel supershift assays. Minimal NF -kappa B activity was observed following exposure of C3H/HeJ macrophag es to lipopolysaccharide. The antioxidant dimethyl sulfoxide decreased the level of NF-kappa B activation in the J774 cells. This correlated with decreased expression of cytokine mRNAs and tumor necrosis factor bioactivity. These results suggest that modulation of NF-kappa B acti vation may provide a mechanism through which antioxidants protect agai nst endotoxemia in murine models.