The inhibitory action of sodium arsenite on lipopolysaccharide-induced nitric oxide production in RAW 267.4 macrophage cells: A role of Raf-1 in lipopolysaccharide signaling

The effect of sodium arsenite (SA) on LPS-induced NO production in RAW 267. 4 murine macrophage cells was studied. SA pretreatment of LPS-stimulated RA W cells resulted in a striking reduction in NO production. No significant d ifference in LPS binding was observed between RAW cells pretreated with SA and control untreated RAW cells, suggesting that SA might impair the intrac ellular signal pathway for NO production. SA inhibited LPS-induced NF-kappa B activation by preventing loss of I kappaB-alpha and -beta, Furthermore, S A blocked phosphorylation of extracellular signal-regulated kinase 1/2 (Erk 1/2), but not phosphorylation of p38 and c-Jun N-terminal kinase, SA treatm ent resulted in the disappearance of Raf-l, suggesting that it might cause the inhibition of the Erk1/2 mitogen-activated protein (MAP) kinase pathway . The SA-mediated loss of Raf-l also abolished LPS-induced NF-kappaB activa tion as well as the Erk1/2 pathway. The dominant negative mutant of MAP kin ase kinase 1 inhibited both NO production and NF-kappaB activation in LPS-s timulated RAW cells. Taken together, these results indicate that the inhibi tory action of SA on NO production in LPS-stimulated macrophages might be d ue to abrogation of inducible NO synthase induction, and it might be closel y related to inactivation of the NF-kappaB and Erk1/2 MAP kinase pathways t hrough loss of Raf-1.