The role of IFIT-2 in local and systemic inflammation
Final Report Abstract
Type interferons (IFN-α, IFN-β) play an important role in antiviral defense, tumor defense and are also involved in sepsis, multiple sclerosis or lupus erythematodes. The action of interferons is mediated by expression of a multitude of interferon stimulated genes (ISGs) and parts of the IFN response acts then for instance to defeata specific virus. In this project we focused on the role of the ISGs, namely interferon-induced tetratricopeptide repeat protein (IFIT2). To study IFIT2, IFIT2 deficient mice were generated. IFIT2 mice are viable and fertile. For further phenotyping see www.europhenome.org. 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. We 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 and β-receptor (IFNAR)- 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. In addition, the role of IFIT2 was analysed in the DSS colitis model, a common and simple model used to study inflammatory bowel disease. By using IFIT2 deficient mice, it could be shown that IFIT2 significantly contributes to IBD development. DSS induces IFIT2 expression in an IFN-λ and type I interferon dependent manner. After DSS treatment, IFN-λ induced IFIT2 is expressed in epithelial cells and not yet defined leukocytes and type I interferon induced IFIT2 in not yet defined leukocytes in the lamina propria.Further studies should address the contribution of both Type I and type III induced IFIT2 for IBD development. IFIT2 might represent a target for treatment of IBD. Further projects are planned: to continue the studies regarding the role of IFIT2 in IBD and to assess the potential for therapeutic approaches; to address in more the details how IFIT2 affects mechanistically the proinflammtory response; to define in cooperation with other groups the role of IFIT2 in other disease model such as experimental autoimmune encephalitis.
Publications
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IFIT2 is an Effector Protein type I IFN-Mediated Amplification of LPS-Induced TNF-a Secretion and LPS-Induced Endotoxin Shock. J Immunol 2013 Sep 6. [Epub ahead of print]
Siegfried A, Berchtold S, Manncke B, Deuschle E, Reber J, Ott T, Weber M, Kalinke U, Hofer JM, Hatesuer B, Schughart K, Gailus-Durner, Fuchs H, Hrabe de Angelis M, Weber F, Hornef MW, Autenrieth IB, Bohn E
