Journalartikel

Jahr der Veröffentlichung: 2013

Seiten: 3913-3921

Zeitschrift: The Journal of Immunology

Bandnummer: 191

Heftnummer: 7

ISSN: 0022-1767

DOI Link: https://doi.org/10.4049/jimmunol.1203305

Verlag: American Association of Immunologists

Abstract: 

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.

Harvard-Zitierstil: Siegfried, A., Berchtold, S., Manncke, B., Deuschle, E., Reber, J., Ott, T., et al. (2013) IFIT2 Is an Effector Protein of Type I IFN–Mediated Amplification of Lipopolysaccharide (LPS)-Induced TNF-α Secretion and LPS-Induced Endotoxin Shock, The Journal of Immunology, 191(7), pp. 3913-3921. https://doi.org/10.4049/jimmunol.1203305

APA-Zitierstil: Siegfried, A., Berchtold, S., Manncke, B., Deuschle, E., Reber, J., Ott, T., Weber, M., Kalinke, U., Hofer, M., Hatesuer, B., Schughart, K., Gailus-Durner, V., Fuchs, H., de Angelis, M., Weber, F., Hornef, M., Autenrieth, I., & Bohn, E. (2013). IFIT2 Is an Effector Protein of Type I IFN–Mediated Amplification of Lipopolysaccharide (LPS)-Induced TNF-α Secretion and LPS-Induced Endotoxin Shock. The Journal of Immunology. 191(7), 3913-3921. https://doi.org/10.4049/jimmunol.1203305