Type I interferon drives tumor necrosis factor–induced lethal shock

Abstract

Tumor necrosis factor (TNF) is reputed to have very powerful antitumor effects, but it is also a strong proinflammatory cytokine. Injection of TNF in humans and mice leads to a systemic inflammatory response syndrome with major effects on liver and bowels. TNF is also a central mediator in several inflammatory diseases. We report that type I interferons (IFNs) are essential mediators of the lethal response to TNF. Mice deficient in the IFN-α receptor 1 (IFNAR-1) or in IFN-β are remarkably resistant to TNF-induced hypothermia and death. After TNF injection, IFNAR-1−/− mice produced less IL-6, had less bowel damage, and had less apoptosis of enterocytes and hepatocytes compared with wild-type (WT) mice. Extensive gene expression analysis in livers of WT and IFNAR-1−/− mice revealed a large deficiency in the response to TNF in the knockout mice, especially of IFN-stimulated response element–dependent genes, many of which encode chemokines. In livers of IFNAR-1−/− mice, fewer infiltrating white blood cells (WBCs) were detected by immunohistochemistry. Deficiency of type I IFN signaling provided sufficient protection for potentially safer therapeutic use of TNF in tumor-bearing mice. Our data illustrate that type I IFNs act as essential mediators in TNF-induced lethal inflammatory shock, possibly by enhancing cell death and inducing chemokines and WBC infiltration in tissues.

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

“…Surprisingly, the lethality associated with LPS challenge was significantly reduced in Ifit2-deficient mice compared with wildtype mice. In accordance, Ifnar 2/2 mice were also significantly more resistant against LPS challenge (11). These findings identify IFIT2 as an effector of the IFN-induced enhancement of LPSmediated lethality.…”

“…In particular, type I IFNs are essential mediators of the lethal response caused by TNF-a. Accordingly, Ifnar-deficient mice are resistant against Tnf-a-induced hypothermia and death (11). Additionally, Ifnar-deficient mice are protected from death in an antitumor therapy approach using rTnf-a (11).…”

“…Interestingly, IFN binding to IFNAR amplifies the secretion of cytokines such as TNF-a and IL-6 (7,8). Also in vivo, type I IFN was shown to promote the development of septic shock using models of LPS challenge or bacterial infection (9)(10)(11). The molecular mechanisms and signaling intermediates of the crosstalk between IFN signaling and the induction of sepsis-inducing cytokines, however, have remained ill defined.…”

Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium

“…Recently, a role for necroptosis in TNF-induced toxicity was uncovered (21), but earlier work stresses the importance of TNFmediated induction of inflammation (e.g., classical antiinflammatory drugs such as steroids and indomethacin protect against TNF toxicity; refs. 22,23) and of inflammatory mediators, such as IL-17, IL-1, IFN-β, ROS, and iNOS (24)(25)(26)(27)(28). Multiple organs, such as intestine, liver, and kidney, suffer from the TNF-induced effects, but it is still unclear which cell type is essential in mediating/initiating the TNF-induced toxicity (2,29,30).…”

Розвиток Імунної Відповіді При Стафілококовій Пневмонії (Частина 3)

“…Активация STAT1 связана с ингибированием факторов транскрипции: про-теина 3, связывающего последовательность GATA (GATA binding protein 3 -GATA-3), ретиноид-свя-занного рецептора γt (RAR related orphan receptor γt -RORγt), и усилением экспрессии генов: специ-фического для T-клеток фактора транскрипции (T-BET -T-cell-specific T-box transcription factor), молекулы CD274 и IL-10. Активация фактора транскрипции STAT3 также приводит к экспрес-сии IL-10, а возбуждение МАРК-ассоциированного сигнального пути -к индукции IL-10 и IL-21 [45]. В соответствии с дуальной ролью IL-27 предотвра-щает повреждение ткани, вызванное чрезмерным воспалением [131].…”