Nitric oxide preferentially induces type 1 T cell differentiation by selectively up-regulating IL-12 receptor beta 2 expression via cGMP.
Nitric oxide plays an important role in immune regulation. We have shown that although high concentrations of NO generally were immune-suppressive, low concentrations of NO selectively enhanced the differentiation of T helper (Th)1 cells but not Th2 cells. This finding provided an explanation for the crucial role of NO in defense against intracellular pathogens. However, the mechanism for the selective induction of Th1 cells was unknown. We report here that at low concentrations, NO activates soluble guanylyl cyclase, leading to the up-regulation of cGMP, which selectively induces the expression of IL-12 receptor beta2 but has no effect on IL-4 receptor. Because IL-12 and IL-4 are the key cytokines for induction of Th1 and Th2 cells, respectively, these results, therefore, provide the mechanism for the selective action of NO on T cell subset differentiation. Furthermore, this selectivity also applies to CD8+ cytotoxic and human T cells and, thus, demonstrates the general implication of this observation in immune regulation. Our results also provide an example of the regulation of cytokine receptor expression by NO. The selectivity of such action via cGMP suggests that it is amenable to therapeutic intervention.
Niedbala
Wanda
W
Department of Immunology and Bacteriology, University of Glasgow, Glasgow G11 6NT, United Kingdom.
Wei
Xiao-Qing
XQ
Campbell
Carol
C
Thomson
Duncan
D
Komai-Koma
Mousa
M
Liew
Foo Y
FY
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured / Q000187:drug effects; D006152:Cyclic GMP / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018448:Models, Immunological; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009603:Nitroso Compounds / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011810:Quinoxalines / Q000494:pharmacology; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000235:genetics; D053707:Receptors, Interleukin-12; D019948:Receptors, Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; C508439:IL12RB2 protein, human; C508443:Il12rb2 protein, mouse; C093285:NOC 18; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D010069:Oxadiazoles; D011810:Quinoxalines; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D019948:Receptors, Interleukin-4; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP