Abstract
IL-12 and IL-18 are both proinflammatory cytokines that contribute to promoting Th1 development and IFN-gamma expression. However, neither IL-12R nor IL-18R is expressed as a functional complex on most resting T cells. This study investigated the molecular mechanisms underlying the induction of an IL-18R complex in T cells. Resting T cells expressed IL-18Ralpha chains but did not exhibit IL-18 binding sites as detected by incubation with rIL-18 followed by anti-IL-18 Ab, suggesting a lack of IL-18Rbeta expression in resting T cells. Although they also failed to express IL-12R, stimulation with anti-CD3 plus anti-CD28 generated IL-12R. Exposure of these cells to IL-12 led not only to up-regulation of IL-18Ralpha expression but also to induction of IL-18R binding sites on both CD4(+) and CD8(+) T cells concomitant with IL-18Rbeta mRNA expression. The IL-18 binding site represented a functional IL-18R complex capable of exhibiting IL-18 responsiveness. IL-12 induction of an IL-18R complex and IL-18Rbeta mRNA expression was not observed in STAT4-deficient (STAT4(-/-)) T cells and was substantially decreased in IFN-gamma(-/-) T cells. However, the failure of STAT4(-/-) T cells to induce an IL-18R complex was not corrected by IFN-gamma. These results indicate that STAT4 and IFN-gamma play an indispensable role and a role as an amplifying factor, respectively, in IL-12 induction of the functional IL-18R complex.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / biosynthesis
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Adjuvants, Immunologic / deficiency
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Adjuvants, Immunologic / genetics
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Adjuvants, Immunologic / physiology*
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Animals
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Binding Sites / genetics
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Binding Sites / immunology
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Cells, Cultured
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Interferon-gamma / biosynthesis
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Interferon-gamma / deficiency
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Interferon-gamma / genetics
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Interferon-gamma / physiology*
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Interleukin-12 / metabolism
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Interleukin-12 / physiology*
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Interleukin-18 Receptor alpha Subunit
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Interphase / genetics
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Interphase / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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NF-kappa B / metabolism
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RNA, Messenger / biosynthesis
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Receptors, Antigen, T-Cell / physiology
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Receptors, Interleukin / biosynthesis*
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Receptors, Interleukin / metabolism
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Receptors, Interleukin-18
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STAT4 Transcription Factor
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Signal Transduction / immunology*
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Trans-Activators / deficiency
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Trans-Activators / genetics
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Trans-Activators / physiology*
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Up-Regulation / immunology
Substances
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Adjuvants, Immunologic
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DNA-Binding Proteins
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Il18r1 protein, mouse
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Interleukin-18 Receptor alpha Subunit
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NF-kappa B
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RNA, Messenger
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Receptors, Antigen, T-Cell
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Receptors, Interleukin
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Receptors, Interleukin-18
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STAT4 Transcription Factor
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Stat4 protein, mouse
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Trans-Activators
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Interleukin-12
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Interferon-gamma