BACTERIAL SUPERANTIGEN-INDUCED HUMAN LYMPHOCYTE-RESPONSES ARE NITRIC-OXIDE DEPENDENT AND MEDIATED BY IL-12 AND IFN-GAMMA

Bacterial superantigens cause marked proliferation of T cells and rele ase of lymphokines, Nitric oxide, derived from the conversion of L-arg inine to L-citrulline, inhibits this activation in murine cells, We ha ve now investigated the roles of IL-12, IFN-gamma, lymphotoxin-alpha, and nitric oxide during superantigen-induced human lymphocyte activati on, Lymphocyte activation was determined by measurement of proliferati ve responses and lymphokine release, Both toxic shock syndrome toxin-1 from Staphylococcus aureus and recombinant streptococcal pyrogenic ex otoxin A induced proliferation and production of IFN-gamma, lymphotoxi n-alpha, and IL-12 by human mononuclear cells in a time-dependent fash ion, The release of IFN-gamma was abrogated by a neutralizing Ab to IL -12, but lymphocyte proliferative responses were unaffected, A neutral izing Ab to IFN-gamma prevented the release of lymphotoxin-alpha, but did not affect proliferation, The neutralization of lymphotoxin-alpha using two different Abs did not affect IFN-gamma release or proliferat ion. In contrast to previous findings in mice, the arginine analogue, N-G-monomethyl-L-arginine, significantly inhibited both proliferation and lymphokine release by superantigen-stimulated human cells, Thus, t he release of lymphotoxin-alpha by lymphocytes following superantigen stimulation is dependent upon the presence of IFN-gamma; the IFN-gamma response is in turn under the control of IL-12, There is no evidence that nitric oxide plays an inhibitory role during superantigen-mediate d human lymphocyte activation, Indeed, arginine is a prerequisite for such activation.