INHIBITION OF MACROPHAGE IA EXPRESSION BY NITRIC-OXIDE

Bacterial LPS inhibits the expression of Ia by macrophages stimulated by IFN-gamma. We now present the following observations that suggest a causal relationship between nitric oxide (NO) and this inhibition of Ia expression: 1) NO production precedes inhibition of Ia, 2) the abil ity of LPS to inhibit Ia expression by IFN-gamma stimulated macrophage s is correlated in a dose-dependent fashion with NO production, 3) Ia expression is restored if NO production is inhibited by N-G-monomethyl -L-arginine or culturing the macrophages in L-arginine-free medium, an d 4) exogenous NO inhibits IFN-gamma-stimulated Ia expression. Taken t ogether these experiments indicate that NO inhibits macrophage express ion of Ia. Furthermore, the following studies showed that inhibition o f Ia by NO was not due to macrophage death: trypan blue exclusion, mac rophage adhesion, conversion of the tetrazolium dye (MTT) to its forma zan by a functioning electron transport system, and phagocytosis of Ig G opsonized SRBCs. By inhibiting Ia expression, NO may inhibit Ag-pres entation to T cells, secretion of IFN-gamma by these T cells, and ulti mately inhibit the IFN-gamma-dependent production of NO synthetase. Th is inhibitory mechanism may prevent excessive NO formation and tissue injury.