| Autor: |
Siegfried A; Interfakultäres Institut für Mikrobiologie und Infektionsmedizin, Eberhard Karl Universität Tuebingen, 72076 Tuebingen, Germany;, Berchtold S, Manncke B, Deuschle E, Reber J, Ott T, Weber M, Kalinke U, Hofer MJ, Hatesuer B, Schughart K, Gailus-Durner V, Fuchs H, Hrabe de Angelis M, Weber F, Hornef MW, Autenrieth IB, Bohn E |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2013 Oct 01; Vol. 191 (7), pp. 3913-21. Date of Electronic Publication: 2013 Sep 06. |
| DOI: |
10.4049/jimmunol.1203305 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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