Research ArticleImmunology

Noncanonical STAT1 phosphorylation expands its transcriptional activity into promoting LPS-induced IL-6 and IL-12p40 production

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Science Signaling  24 Mar 2020:
Vol. 13, Issue 624, eaay0574
DOI: 10.1126/scisignal.aay0574

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Inflammatory internalization

When bound to its ligand LPS, the cell surface pattern recognition receptor TLR4 stimulates the production of proinflammatory cytokines. However, endocytosed TLR4 signals through different effectors to drive production of interferon-β (IFN-β), an antiviral cytokine. Metwally et al. found an alternative signaling pathway activated by endocytosed TLR4 in mouse and human macrophages that contributed to the production of the proinflammatory cytokines IL-6 and IL-12p40 independently of IFN-β. Endocytosis of TLR4 led to the noncanonical phosphorylation of the transcriptional regulator STAT1, which altered its target DNA motif. STAT1 stimulated the expression of the genes encoding IL-12p40 and the protein ARID5A, which increased the stability of IL6 mRNA. Together, these findings suggest how endocytosed TLR4 contributes to proinflammatory cytokine production, which may have implications for the use of vaccine adjuvants that target this receptor.

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