Article abstract
Nature Immunology 9, 378 - 387 (2008)
Published online: 16 March 2008 | doi:10.1038/ni1576
TNF activates an IRF1-dependent autocrine loop leading to sustained expression of chemokines and STAT1-dependent type I interferon–response genes
Anna Yarilina1, Kyung-Hyun Park-Min1, Taras Antoniv1, Xiaoyu Hu1 & Lionel B Ivashkiv1,2
Abstract
Rapid induction of inflammatory genes by tumor necrosis factor (TNF) has been well studied, but little is known about delayed and chronic TNF responses. Here we investigated the kinetics of primary macrophage responses to TNF and discovered that TNF initiates an interferon-
-mediated autocrine loop that sustains expression of inflammatory genes and induces delayed expression of interferon-response genes such as those encoding the transcription factors STAT1 and IRF7, which enhance macrophage responses to stimulation of cytokines and Toll-like receptors. TNF-induced interferon- production depended on interferon-response factor 1, and downstream gene expression was mediated by synergy between small amounts of interferon- and canonical TNF-induced signals. Thus, TNF activates a 'feed-forward' loop that sustains inflammation but avoids the potential toxicity associated with the high interferon production induced by stimulation of Toll-like receptors.
- Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York 10021, USA.
- Graduate Program in Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences of Cornell University, New York, New York 10021, USA.
Correspondence to: Lionel B Ivashkiv1,2 e-mail: ivashkivl@hss.edu
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