Gi-Protein-Dependent Inhibition of IL-12 Production Is Mediated by Activation of the Phosphatidylinositol 3-Kinase-Protein 3 Kinase B/Akt Pathway and JNK

DOI PDF 被引用文献3件
  • Andrea la Sala
    Mucosal Immunobiology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892
  • Massimo Gadina
    Department of Microbiology and Immunology, Queen’s University of Belfast , Belfast ,
  • Brian L Kelsall
    Mucosal Immunobiology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892

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公開日
2005-09-01
権利情報
  • https://academic.oup.com/pages/standard-publication-reuse-rights
DOI
  • 10.4049/jimmunol.175.5.2994
公開者
Oxford University Press (OUP)

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<jats:title>Abstract</jats:title> <jats:p>Ligands for certain Gi-protein-coupled receptors (GiPCRs) potently inhibit the production of IL-12 by human monocytes. We addressed the intracellular signaling mechanisms by which this occurs using primary human cells. Stimulation with the GiPCR ligands C5a and 1-deoxy-1-[6-[(3-iodophenyl)methyl]amino]-9H-purine-9-y1]-N-methyl-β-d-ribofuranuronamide (IB-MECA) blocked the production of IL-12 p70 by human monocytes stimulated with LPS and IFN-γ. In addition, C5a reduced the expression of mRNA for IL-12 p35, p40, IL-23 p19, and IL-27 p28. This effect was due neither to a down-regulation of TLR4 or IFN-γ receptor on the cell surface nor to interference with IFN-γ signaling, because IFN-γ-induced up-regulation of HLA-DR and CD40 were unaffected. C5a or IB-MECA activated the PI3K/Akt signaling pathway and induced the phosphorylation of the MAPK p38, ERK, and JNK. Inhibition of the PI3K/Akt signaling pathway with wortmannin or an inhibitor of Akt activity, and inhibition of JNK but not ERK prevented IL-12 and IL-23 suppression by C5a. These data extend observations on IL-12 suppression by C5a to IL-23 and IL-27, and are the first to demonstrate the intracellular signaling events leading to IL-12 and IL-23 inhibition after GiPCR activation.</jats:p>

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