Inhibition of the reactive proliferation of lymphocytes by activated macrophages: the role of nitric oxide

Abstract

The effects of nitric oxide synthesis by activated macrophages on concanavalin A (Con A) stimulated lymphocyte proliferation and the modulation of these events by extraneous L-arginine concentration were investigated. In 1 mM or 5 mM exogenous L-arginine, inhibition of proliferation of a fixed number of lymphocytes was progressively inhibited in the presence of increasing numbers of macrophages. This inhibition was related to increased nitric oxide synthesis by the macrophages and was suppressed in the presence of NG-monomethyl-L-arginine (NMMA), a specific inhibitor of nitric oxide synthesis. Inhibition of nitric oxide synthesis by 500 microM NMMA was less effective at high concentrations of macrophages, and in 5 mM as compared with 1 mM L-arginine. In the absence of exogenous L-arginine, NMMA inhibited lymphocyte proliferation in the presence of low numbers of macrophages but appeared to promote proliferation at high macrophage concentrations. Membrane separation of lymphocytes and macrophages led to loss of the nitric oxide mediated inhibitory effect on lymphocyte division except at the highest concentrations of macrophages used. Inhibition of lymphocyte proliferation could not be associated with L-arginine depletion of the media by macrophages or by the action of nitrite ions, a product of nitric oxide oxidation.