Nitric oxide preferentially induces type 1 T cell differentiation by selectively up-regulating IL-12 receptor beta 2 expression via cGMP

Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16186-91. doi: 10.1073/pnas.252464599. Epub 2002 Nov 25.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Cells, Cultured / drug effects
  • Cyclic GMP / physiology*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gene Expression Regulation / drug effects
  • Guanylate Cyclase / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Immunological
  • Nitric Oxide / pharmacology*
  • Nitric Oxide Donors / pharmacology
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitroso Compounds / pharmacology
  • Oxadiazoles / pharmacology
  • Polymerase Chain Reaction
  • Quinoxalines / pharmacology
  • Receptors, Interleukin / biosynthesis*
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin-12
  • Receptors, Interleukin-4 / biosynthesis
  • Receptors, Interleukin-4 / genetics
  • Signal Transduction / drug effects
  • Th1 Cells / cytology
  • Th1 Cells / drug effects*
  • Th1 Cells / immunology
  • Th2 Cells / drug effects

Substances

  • 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
  • Enzyme Inhibitors
  • IL12RB2 protein, human
  • Il12rb2 protein, mouse
  • NOC 18
  • Nitric Oxide Donors
  • Nitroso Compounds
  • Oxadiazoles
  • Quinoxalines
  • Receptors, Interleukin
  • Receptors, Interleukin-12
  • Receptors, Interleukin-4
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Guanylate Cyclase
  • Cyclic GMP