Nitric oxide selectively decreases interferon-gamma expression by activated human T lymphocytes via a cGMP-independent mechanism

The role of exogenous nitric oxide (NO) on the expression of interleukin (I L)-2, IL-4, IL-5 and interferon-gamma (IFN-gamma) by freshly isolated human T lymphocytes was investigated. The presence of NO, generated from any of the NO-donor compounds, S-nitroso-N-acetyl-D,L-penicillamine (NAP), DPTA-no noate (DPTA) or DETA-nonoate (DETA), added 15 min prior to T-cell stimulati on (for 24 hr) with anti-CD3/anti-CD28 monoclonal antibodies (mAbs), result ed in up to 50% inhibition of IL-4, IL-5 and IFN-gamma secretion. In contra st, IL-2 secretion was not inhibited. Using the guanylate cyclase inhibitor , LY83583, it was shown that the inhibition of IL-4 and IL-5 was cGMP depen dent, whereas additional mechanisms mediated the inhibition of IFN-gamma. E xposure of T cells to the NO-donor compounds for 24 hr prior to stimulation resulted in a more pronounced inhibition of IFN-gamma secretion by DPTA an d DETA (P < 0.01), despite the fact that NO generation could no longer be d etected. Under these conditions, IL-4 secretion was not inhibited and IL-5 secretion was inhibited to a lesser extent(P < 0.01 for SNAP and DPTA, P > 0.05 for DETA). IL-2 secretion was inhibited after 24 hr of preincubation w ith the NO-donor compounds, whereas it was not directly affected by NO. The increased inhibitory effects on IFN-gamma and IL-2 secretion could not be accounted for by the antiproliferative effects of the NO-donor compounds, w hich were diminished after 24 hr of preincubation relative to 15 min of pre incubation. For IFN-gamma, the inhibition was at least partially effected a t the transcriptional level as shown by decreased mRNA accumulation. These data show that NO can modulate the balance between the expression, by human T-lymphocytes, of T helper 1- and T helper 2-type cytokines, through selec tive and persistent inhibition of the expression of IFN-gamma via a cGmP-in dependent mechanism.