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 (IL)-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 (SNAP), DPTA-nonoate (DPTA) or DETA-nonoate (DETA), added 15 min prior to T-cell stimulation (for 24 hr) with anti-CD3/anti-CD28 monoclonal antibodies (mAbs), resulted in up to 50% inhibition of IL-4, IL-5 and IFN-gamma secretion. In contrast, 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 dependent, whereas additional mechanisms mediated the inhibition of IFN-gamma. Exposure 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 and DETA (P < 0.01), despite the fact that NO generation could no longer be detected. 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 with 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, which were diminished after 24 hr of preincubation relative to 15 min of preincubation. For IFN-gamma, the inhibition was at least partially effected at 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 selective and persistent inhibition of the expression of IFN-gamma via a cGMP-independent mechanism.
Roozendaal
R
R
Division of Allergology, University Hospital Groningen, The Netherlands.
Vellenga
E
E
Postma
D S
DS
De Monchy
J G
JG
Kauffman
H F
HF
D000634:Aminoquinolines / Q000494:pharmacology; D002455:Cell Division; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D003671:DEET / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D000634:Aminoquinolines; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D015848:Interleukin-5; D020030:Nitric Oxide Donors; D012333:RNA, Messenger; C110881:S-nitro-N-acetylpenicillamine; D003671:DEET; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma; C041715:6-anilino-5,8-quinolinedione; D006162:Guanylate Cyclase; D010396:Penicillamine; D006152:Cyclic GMP