title: Role of IFN-gamma in Th1 differentiation: IFN-gamma regulates IL-18R alpha expression by preventing the negative effects of IL-4 and by inducing/maintaining IL-12 receptor beta 2 expression.
abstract: Two key events occur during the differentiation of IFN-gamma-secreting Th1 cells: up-regulation of IL-12Rbeta2 and IL-12-driven up-regulation of IL-18Ralpha. We previously demonstrated that IL-12-driven up-regulation of IL-18Ralpha expression is severely impaired in IFN-gamma(-/-) mice. However, it was unclear from these studies how IFN-gamma influenced IL-18Ralpha since IFN-gamma alone had no direct effect on IL-18Ralpha expression. In the absence of IL-4, IL-12-dependent up-regulation of IL-18Ralpha/IL-12Rbeta2 was independent of IFN-gamma. However, in the presence of IL-4, IFN-gamma functions to limit the negative effects of IL-4 on both IL-18Ralpha and IL-12Rbeta2. Neutralization of IL-4 restored IL-12-driven up-regulation of IL-18Ralpha/IL-12Rbeta2 in an IFN-gamma-independent fashion. In the absence of both IL-12 and IL-4, IFN-gamma up-regulates IL-12beta2 expression and primes IFN-gamma-producing Th1 cells. When T cells were primed in the presence of IL-4, no correlation was found between the levels of expression of the IL-18Ralpha or the IL-12Rbeta2 and the capacity of these cells to produce IFN-gamma, suggesting that IL-4 may also negatively affect IL-12-mediated signal transduction and thus Th1 differentiation. These data clarify the role of IFN-gamma in regulation of IL-18Ralpha/IL-12Rbeta2 during both IL-12-dependent and IL-12-independent Th1 differentiation.
authors.affiliation: Laboratory of Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Smeltz
authors.forename: June
authors.initials: J
authors.lastname: Chen
authors.forename: Rolf
authors.initials: R
authors.lastname: Ehrhardt
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Shevach
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D005260:Female; D007371:Interferon-gamma / Q000502:physiology*; D018664:Interleukin-12 / Q000378:metabolism* / Q000502:physiology; D020382:Interleukin-18 / Q000378:metabolism*; D053727:Interleukin-18 Receptor alpha Subunit; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018123:Receptors, Interleukin / Q000096:biosynthesis*; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; C508573:Il18r1 protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; C499308:Rag2 protein, mouse; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; C064655:V(D)J recombination activating protein 2; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma