| First Author | Siegfried A | Year | 2013 |
| Journal | J Immunol | Volume | 191 |
| Issue | 7 | Pages | 3913-21 |
| PubMed ID | 24014876 | Mgi Jnum | J:199862 |
| Mgi Id | MGI:5505701 | Doi | 10.4049/jimmunol.1203305 |
| Citation | Siegfried A, et al. (2013) IFIT2 is an effector protein of type I IFN-mediated amplification of lipopolysaccharide (LPS)-induced TNF-alpha secretion and LPS-induced endotoxin shock. J Immunol 191(7):3913-21 |
| abstractText | Type I IFN signaling amplifies the secretion of LPS-induced proinflammatory cytokines such as TNF-alpha 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-alpha receptor- and IFN regulatory factor (Irf)9-dependent manner. Also, LPS induced secretion of IL-6 and TNF-alpha 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-alpha 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-beta mRNA expression and Ifit2 protein expression after LPS stimulation was found. Also, Tnf-alpha and Il-6 secretion but not Tnf-alpha 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. |
