IFIT2 Is an Effector Protein of Type I IFN–Mediated Amplification of Lipopolysaccharide (LPS)-Induced TNF-α Secretion and LPS-Induced Endotoxin Shock

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.

Increased Antigen Presentation but Impaired T Cells Priming after Upregulation of Interferon-Beta Induced by Lipopolysaccharides Is Mediated by Upregulation of B7H1 and GITRL

“…Despite nicotine augmented 1.6 and 1.3 folds expression of CD11c and MHC class II, LPS treatment increased about 2.7 and 2.8 folds up-regulation of these molecules, which are in line with previous reports [12], indicating that DCs used in our studies is relatively immature DCs. Apart from immune cells, endothelial cell, fibroblast and other cells were also reported to express IFN-beta and other cytokines in LPS stimulated condition [45]–[47]. Hence, despite our studies demonstrated that IFN-beta contributes to LPS-induced DCs paralysis, it cannot exclude the possibilities that IFN-beta and other cytokines expressed by other cells facilitate pathogen-induced DCs’ paralysis, which awaits further investigation.…”

The Chlamydia trachomatis Type III Secretion Chaperone Slc1 Engages Multiple Early Effectors, Including TepP, a Tyrosine-phosphorylated Protein Required for the Recruitment of CrkI-II to Nascent Inclusions and Innate Immune Signaling

“…In murine macrophages, overexpression of IFIT2 represses lipopolysaccharide (LPS) induced TNF- α and IL-6 expression [65]. In contrast, IFIT2 −/− mice display reduced TNF- α and IL-6 in serum and LPS-mediated lethality in an endotoxic shock model, suggesting IFIT2 is a critical mediator for the secretion of LPS-induced proinflammatory cytokines [66]. In C. trachomatis , both IFIT1 and IFIT2 genes were reported to be up-regulated more than 10 fold in HeLa 229 cells by 16 hpi [67].…”

Tyrosine phosphorylation in Toll-like receptor signaling

“…A specific cytokine, IFN-β, induced by TLR4 signaling, is associated with TLR4-mediated sepsis (41). An ISG, Ifit2, has recently been shown to be a potential effector of TLR4-mediated sepsis (42). The expression of TLR3 and TLR4 in intestinal epithelium is altered in active IBD and specific polymorphism in the TLR4 gene has been associated with Crohn’s disease and ulcerative colitis (43).…”