MACROPHAGE-DERIVED NITRIC-OXIDE REGULATES T-CELL ACTIVATION VIA REVERSIBLE DISRUPTION OF THE JAK3 STAT5 SIGNALING PATHWAY/

Nitric oxide (NO) has been invoked as an important pathogenic factor i n a wide range of immunologically mediated diseases. The present study demonstrates that macrophage-derived NO may conversely function to fi ne tune T cell-mediated inflammation via reversible dephosphorylation of intracellular signaling molecules, which are involved in the contro l of T cell proliferation. Thus, T cells activated in the presence of alveolar macrophages are unable to proliferate despite expression of I L-2R and secretion of IL-2. This process is reproduced by the NO gener ator S-nitroso-N-acetylpenicillamine and is inhibitable by the NO synt hase inhibitor N-G-methyl-L-arginine. Analysis of T cell lysates by im munoprecipitation with specific Abs and subsequent immunoblotting indi cated marked reduction of tyrosine phosphorylation of Jak3 and STAT5 m ediated by NO. Further studies indicated that NO-mediated T cell suppr ession was reversible by the guanylate cyclase inhibitors methylene bl ue and LY-83583 and was reproduced by a cell-permeable analogue of cyc lic GMP, implicating guanylate cyclase activation as a key step in the inhibition of T cell activation by NO.