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MyD88-mediated stabilization of interferon-γ-induced cytokine and chemokine mRNA

Nature Immunology volume 7, pages 375–381 (2006)Cite this article

Abstract

The MyD88 adaptor protein is critical in Toll-like receptor and interleukin 1 receptor (IL-1R) signaling, but has not been linked to interferon-γ receptor (IFN-γR) signaling. Here we demonstrate that MyD88 increased the half-life but not the synthesis of IFN-γ-induced mRNA transcripts encoding tumor necrosis factor and IFN-γ-inducible protein 10. IFN-γ stimulation triggered a physical association between the IFN-γR1 and MyD88. Transcript stabilization required activation of mixed-lineage kinase 3 and p38 mitogen-activated protein kinase and the presence of an adenine-uridine–rich element in the transcript's 3′ untranslated region. These results demonstrate a MyD88-dependent post-transcriptional mechanism through which IFN-γ can enhance the expression of genes encoding proinflammatory molecules.

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Figure 1: Defective IFN-γ-induced IP-10 expression in the absence of MyD88.
Figure 2: Normal IFN-γ-induced transcriptional activity but reduced mRNA stability in Myd88−/− macrophages.
Figure 3: Signaling molecules involved in the MyD88-dependent stabilization of ARE-containing luciferase reporter constructs.
Figure 4: Association of MyD88 with IFN-γR1, MLK3 and JIP-1.
Figure 5: Effect of p38 and MLK3 on IFN-γ-induced IP-10 expression.

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Acknowledgements

We thank H. Yu for technical assistance, and C. Nathan and K. Rhee for critical reading of the manuscript. Supported by the National Institutes of Health (AI30165 and GM61710 to A.D.) and the William Randolph Hearst Foundation (to The Department of Microbiology and Immunology).

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  1. Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, 10021, New York, USA

    Dongxu Sun & Aihao Ding

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Correspondence to Aihao Ding.

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Sun, D., Ding, A. MyD88-mediated stabilization of interferon-γ-induced cytokine and chemokine mRNA. Nat Immunol 7, 375–381 (2006). https://doi.org/10.1038/ni1308

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