Alachlor and carbaryl suppress lipopolysaccharide-induced iNOS expression by differentially inhibiting NF-kappaB activation

Nitric oxide (NO) produced by macrophages plays an important role in host defense and inflammation. We found that two agrochemicals, alachlor and carbaryl, inhibit lipopolysaccharide (LPS)-induced NO production by macrophages. In the present study, we investigated this inhibitory mechanism in RAW 264 cells. Both chemicals inhibited LPS-induced iNOS protein and mRNA expression as well as murine iNOS promoter activity. When treating these chemicals with reducing agents, the inhibition by carbaryl was reversed, but not the inhibition by alachlor. These chemicals also inhibited LPS-induced interferon-beta (IFN-beta) expression, an indispensable factor for LPS-induced iNOS expression. The inhibited iNOS expression, however, was not restored by exogenous IFN-beta supplementation. LPS-induced nuclear translocation of NF-kappaB, which is necessary for the expression of IFN-beta and iNOS, was inhibited by these chemicals: however, the LPS-induced degradation of IkappaB-alpha and IkappaB-beta was inhibited only by alachlor. These results indicate that alachlor and carbaryl differentially impair the LPS-induced NF-kappaB activation, leading to the inhibition of NO production.