Suppression of lymphocyte proliferation through the nitric oxide synthesizing pathway.

The amino acid L-arginine can be metabolized through a nitric oxide-synthesizing pathway (NOSP) to produce L-citrulline and reactive nitrogen intermediates. Among these nitrogen intermediates, NO has been implicated as the mediator of a variety of biological effects including vasodilatation, inhibition of platelet aggregation, tumor cytotoxicity and microbiostasis by activated macrophages and generalized suppression of macrophage functions. Work reported here demonstrated that the NOSP is expressed in Con A-stimulated rat splenic cell (SC) cultures and is associated with a profound suppression of lymphocyte proliferation. Inhibition of the NOSP by NG-monomethyl-L-arginine (N-MMA) or binding of its products by hemoglobin, either free in solution or contained in RBC, markedly promotes rat SC mitogenic response to Con A. Mouse SC do not express the NOSP under the conditions used in these experiments. Consequently, their mitogenic response to Con A is not affected by N-MMA or hemoglobin. These data confirm and expand the apparent role of NO as a regulator of immune responses while indicating potentially important species differences.