Interferons limit inflammatory responses by induction of tristetraprolin.
Interferons (IFNs) are cytokines with pronounced proinflammatory properties. Here we provide evidence that IFNs also play a key role in decline of inflammation by inducing expression of tristetraprolin (Ttp). TTP is an RNA-binding protein that destabilizes several AU-rich element-containing mRNAs including TNFalpha. By promoting mRNA decay, TTP significantly contributes to cytokine homeostasis. Now we report that IFNs strongly stimulate expression of TTP if a costimulatory stress signal is provided. IFN-induced expression of Ttp depends on the IFN-activated transcription factor STAT1, and the costimulatory stress signal requires p38 MAPK. Within the Ttp promoter we have identified a functional gamma interferon-activated sequence that recruits STAT1. Consistently, STAT1 is required for full expression of Ttp in response to LPS that stimulates both p38 MAPK and, indirectly, interferon signaling. We demonstrate that in macrophages IFN-induced TTP protein limits LPS-stimulated expression of several proinflammatory genes, such as TNFalpha, IL-6, Ccl2, and Ccl3. Thus, our findings establish a link between interferon responses and TTP-mediated mRNA decay during inflammation, and propose a novel immunomodulatory role of IFNs.
Sauer
Ines
I
Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, Dr Bohr-Gasse 9, A-1030 Vienna, Austria.
Schaljo
Barbara
B
Vogl
Claus
C
Gattermeier
Irene
I
Kolbe
Thomas
T
Müller
Mathias
M
Blackshear
Perry J
PJ
Kovarik
Pavel
P
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D007372:Interferons / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D020871:RNA Stability / Q000187:drug effects / Q000276:immunology*; D020218:Response Elements / Q000235:genetics / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology; D051816:Tristetraprolin / Q000235:genetics / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D051816:Tristetraprolin; C497553:Zfp36 protein, mouse; D007372:Interferons; D048051:p38 Mitogen-Activated Protein Kinases