PuSH - Publikationsserver des Helmholtz Zentrums München: IFIT2 is an effector protein of type 1 IFN-mediated amplification of lipopolysaccharide (LPS)-induced TNF-α secretion and LPS-induced endotoxin shock.

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Siegfried, A.* ; Berchtold, S.* ; Manncke , B.* ; Deuschle, E.* ; Reber, J.* ; Ott, T.* ; Weber, M.* ; Kalinke, U.* ; Hofer, M.J.* ; Hatesuer, B.* ; Schughart, K.* ; Gailus-Durner, V. ; Fuchs, H. ; Hrabě de Angelis, M. ; Weber, F.* ; Hornef, M.W.* ; Autenrieth, I.B.* ; Bohn, E.*

IFIT2 is an effector protein of type 1 IFN-mediated amplification of lipopolysaccharide (LPS)-induced TNF-α secretion and LPS-induced endotoxin shock.

J. Immunol. 191, 3913-3921 (2013)

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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.

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Type I IFN signaling amplifies the secretion of LPS-induced proinflammatory cytokines such as TNF-α or IL-6 and might thus contribute to the high mortality associated with Gram-negative septic shock in humans. The underlying molecular mechanism, however, is ill defined. In this study, we report the generation of mice deficient in IFN-induced protein with tetratricopeptide repeats 2 (Ifit2) and demonstrate that Ifit2 is a critical signaling intermediate for LPS-induced septic shock. Ifit2 expression was significantly upregulated in response to LPS challenge in an IFN-α receptor- and IFN regulatory factor (Irf)9-dependent manner. Also, LPS induced secretion of IL-6 and TNF-α by bone marrow-derived macrophages (BMDMs) was significantly enhanced in the presence of Ifit2. In accordance, Ifit2-deficient mice exhibited significantly reduced serum levels of IL-6 and TNF-α and reduced mortality in an endotoxin shock model. Investigation of the underlying signal transduction events revealed that Ifit2 upregulates Irf3 phosphorylation. In the absence of Irf3, reduced Ifn-β mRNA expression and Ifit2 protein expression after LPS stimulation was found. Also, Tnf-α and Il-6 secretion but not Tnf-α and Il-6 mRNA expression levels were reduced. Thus, IFN-stimulated Ifit2 via enhanced Irf3 phosphorylation upregulates the secretion of proinflammatory cytokines. It thereby amplifies LPS-induced cytokine production and critically influences the outcome of endotoxin shock.

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