STIMULATION OF FC-GAMMA RECEPTORS IN RAT PERITONEAL-MACROPHAGES INDUCES THE EXPRESSION OF NITRIC-OXIDE SYNTHASE AND CHEMOKINES BY MECHANISMS SHOWING DIFFERENT SENSITIVITIES TO ANTIOXIDANTS AND NITRIC-OXIDE DONORS

The induction of nitric oxide (NO) production and the expression of cy tokine-induced neutrophil chemoattractant (CINC-1) were studied in rat peritoneal adherent tells stimulated with insoluble immune complexes containing rabbit IgG Ab and OVA as the cognate Ag (IC). Incubation wi th IC at concentrations as low as 10 mu g/ml induced NO production and the expression of inducible NO synthase (iNOS) protein. This was acco mpanied by the expression of CINC-1 mRNA and the activation of nuclear factor-kappa B (NF-kappa B). However, the expression of iNOS and CINC -1 mRNA induced by IC showed a different temporal pattern and a differ ent sensitivity to both the antioxidant agent pyrrolidine dithiocarbam ate (PDTC) and modulation by NO itself. Whereas iNOS mRNA and protein expression were blunted by PDTC and NO-generating compounds, CINC-1 mR NA expression was either enhanced or not affected by PDTC and NO donor s. The time course of NF-KB activation was parallel to that of iNOS in duction and was influenced in the same sense as iNOS induction by anti oxidants, NO donors, the protease inhibitor N-tosyl phenylalanine chlo romethyl ketone, and inhibitors of protein tyrosine phosphorylation re actions. These data indicate the existence in rat macrophages of a sig naling mechanism triggered by Fc gamma R occupancy:that leads to nucle ar signaling, is initiated by protein tyrosine phosphorylation reactio ns, and shows specific sensitivities to antioxidants and NO. Whereas t rans-activation of the iNOS gene can be fully explained by the stimula tion of NF-kappa B, induction of CINC-1 mRNA expression seems influenc ed by additional regulatory elements.