title: IL-12 synergizes with IL-18 or IL-1beta for IFN-gamma production from human T cells.
abstract: IL-18 is a proinflammatory cytokine that plays an important role in NK cell activation and T(h)1 response. IL-18 has a structural homology to IL-1, particularly IL-1beta. IL-18R, composed of IL-1R-related protein (IL-18Ralpha) and IL-1R accessory protein-like (IL-18Rbeta), belongs to the IL-1R family. Furthermore, IL-18R at least partly shares the signal transducing system with IL-1R. Thus, the IL-18-IL-18R system has a striking similarity to the IL-1-IL-1R system. For this reason, we regarded it important to investigate whether, like IL-18, IL-1beta synergizes with IL-12 in inducing IFN-gamma production from human T cells and plays an important role in the T(h)1 response. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R. Then, IL-12-stimulated T cells responded to IL-18 or IL-1beta by their proliferation and IFN-gamma production, although levels of IL-1beta-induced responses were lower. CD4(+)CD45RA(+) T cells, although they constitutively expressed IL-18Rbeta mRNA, did not express IL-18Ralpha mRNA. Phytohemagglutinin (PHA) stimulation alone induced IL-18Ralpha mRNA without affecting the expression of IL-18Rbeta mRNA. T(h)1-inducing conditions (PHA, IL-12 and anti-IL-4) further increased this expression. We also show that T(h)1 cells but not T(h)2 cells have increased expression of IL-18R and IL-1R, and produce IFN-gamma in response to IL-18 and/or IL-1beta.
authors.affiliation: Third Department of Internal Medicine, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya 663-8501, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tominaga
authors.forename: T
authors.initials: T
authors.lastname: Yoshimoto
authors.forename: K
authors.initials: K
authors.lastname: Torigoe
authors.forename: M
authors.initials: M
authors.lastname: Kurimoto
authors.forename: K
authors.initials: K
authors.lastname: Matsui
authors.forename: T
authors.initials: T
authors.lastname: Hada
authors.forename: H
authors.initials: H
authors.lastname: Okamura
authors.forename: K
authors.initials: K
authors.lastname: Nakanishi
mesh_terms: D004357:Drug Synergism; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D053727:Interleukin-18 Receptor alpha Subunit; D008213:Lymphocyte Activation / Q000187:drug effects; D018123:Receptors, Interleukin / Q000378:metabolism; D053724:Receptors, Interleukin-18; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: C508572:IL18R1 protein, human; D007375:Interleukin-1; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma