Interferons limit inflammatory responses by induction of tristetraprolin

Ines Sauer

Barbara Schaljo

Claus Vogl

Irene Gattermeier

^{Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, A-1030 Vienna, Austria}

^{Austrian Center of Biomodelling and Transgenetics, Vienna University of Veterinary Medicine, A-1210 Vienna, Austria}

^{Institute of Animal Breeding and Genetics, Vienna University of Veterinary Medicine, A-1210 Vienna, Austria}

^{Department of Agrobiotechnology, IFA-Tulln, University of Natural Resources and Applied Life Sciences, Vienna}

^{Laboratory of Neurobiology, National Institute of Environmental Health Science, Research Triangle Park, North Carolina 27709, USA}

^{Corresponding author: Pavel Kovarik, Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, Dr. Bohr-Gasse 9, A-1030 Vienna, Austria. Tel.: +43 1 4277 54608; Fax: +43 1 4277 9546;}ta.ca.eivinu@kiravok.levap

Abstract

Interferons (IFNs) are cytokines with pronounced proinflammatory properties. Here we provide evidence that IFNs play a key role also 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 TNFα. By promoting mRNA decay TTP significantly contributes to cytokine homeostasis. Now we report that IFNs strongly stimulate expression of TTP if a co-stimulatory stress signal is provided. IFN-induced expression of TTP depends on the IFN-activated transcription factor STAT1, and the co-stimulatory 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 TNFα, 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.

Keywords: Immunobiology, innate immunity, monocyte and macrophage biology

Abstract

References

1. Sen GCViruses and interferons. Annu Rev Microbiol. 2001;55:255–281.[PubMed][Google Scholar]
2. Bogdan CThe function of type I interferons in antimicrobial immunity. Curr Opin Immunol. 2000;12:419–424.[PubMed][Google Scholar]
3. Schroder K, Hertzog PJ, Ravasi T, Hume DAInterferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75:163–189.[PubMed][Google Scholar]
4. Schindler C, Brutsaert SInterferons as a paradigm for cytokine signal transduction. Cell Mol Life Sci. 1999;55:1509–1522.[PubMed][Google Scholar]
5. Levy DE, Darnell JE., JrStats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3:651–662.[PubMed][Google Scholar]
6. Wen Z, Zhong Z, Darnell JE., JrMaximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995;82:241–250.[PubMed][Google Scholar]
7. Varinou L, Ramsauer K, Karaghiosoff M, Kolbe T, Pfeffer K, Muller M, Decker TPhosphorylation of the Stat1 transactivation domain is required for full-fledged IFN-gamma-dependent innate immunity. Immunity. 2003;19:793–802.[PubMed][Google Scholar]
8. Kovarik P, Stoiber D, Eyers PA, Menghini R, Neininger A, Gaestel M, Cohen P, Decker TStress-induced phosphorylation of STAT1 at Ser727 requires p38 mitogen-activated protein kinase whereas IFN-gamma uses a different signaling pathway. Proc Natl Acad Sci U S A. 1999;96:13956–13961.[Google Scholar]
9. Gollob JA, Schnipper CP, Murphy EA, Ritz J, Frank DAThe functional synergy between IL-12 and IL-2 involves p38 mitogen-activated protein kinase and is associated with the augmentation of STAT serine phosphorylation. J Immunol. 1999;162:4472–4481.[PubMed][Google Scholar]
10. Ramsauer K, Sadzak I, Porras A, Pilz A, Nebreda AR, Decker T, Kovarik Pp38 MAPK enhances STAT1-dependent transcription independently of Ser-727 phosphorylation. Proc Natl Acad Sci U S A. 2002;99:12859–12864.[Google Scholar]
11. Li Y, Sassano A, Majchrzak B, Deb DK, Levy DE, Gaestel M, Nebreda AR, Fish EN, Platanias LCRole of p38alpha Map kinase in Type I interferon signaling. J Biol Chem. 2004;279:970–979.[PubMed][Google Scholar]
12. Iwasaki A, Medzhitov RToll-like receptor control of the adaptive immune responses. Nat Immunol. 2004;5:987–995.[PubMed][Google Scholar]
13. Tracey KJ, Cerami ATumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu Rev Med. 1994;45:491–503.[PubMed][Google Scholar]
14. Feldmann M, Brennan FM, Maini RNRheumatoid arthritis. Cell. 1996;85:307–310.[PubMed][Google Scholar]
15. Anderson P, Phillips K, Stoecklin G, Kedersha NPost-transcriptional regulation of proinflammatory proteins. J Leukoc Biol. 2004[PubMed][Google Scholar]
16. Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias GImpaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity. 1999;10:387–398.[PubMed][Google Scholar]
17. Kotlyarov A, Neininger A, Schubert C, Eckert R, Birchmeier C, Volk HD, Gaestel MMAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis. Nat Cell Biol. 1999;1:94–97.[PubMed][Google Scholar]
18. Kontoyiannis D, Kotlyarov A, Carballo E, Alexopoulou L, Blackshear PJ, Gaestel M, Davis R, Flavell R, Kollias GInterleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology. Embo J. 2001;20:3760–3770.[Google Scholar]
19. Taylor GA, Carballo E, Lee DM, Lai WS, Thompson MJ, Patel DD, Schenkman DI, Gilkeson GS, Broxmeyer HE, Haynes BF, Blackshear PJA pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity. 1996;4:445–454.[PubMed][Google Scholar]
20. Carballo E, Lai WS, Blackshear PJFeedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science. 1998;281:1001–1005.[PubMed][Google Scholar]
21. Mahtani KR, Brook M, Dean JL, Sully G, Saklatvala J, Clark ARMitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor alpha mRNA stability. Mol Cell Biol. 2001;21:6461–6469.[Google Scholar]
22. Suzuki K, Nakajima H, Ikeda K, Maezawa Y, Suto A, Takatori H, Saito Y, Iwamoto IIL-4-Stat6 signaling induces tristetraprolin expression and inhibits TNF-alpha production in mast cells. J Exp Med. 2003;198:1717–1727.[Google Scholar]
23. Ogawa K, Chen F, Kim YJ, Chen YTranscriptional regulation of tristetraprolin by transforming growth factor-beta in human T cells. J Biol Chem. 2003;278:30373–30381.[PubMed][Google Scholar]
24. Carballo E, Lai WS, Blackshear PJEvidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability. Blood. 2000;95:1891–1899.[PubMed][Google Scholar]
25. Tchen CR, Brook M, Saklatvala J, Clark ARThe stability of tristetraprolin mRNA is regulated by mitogen activated protein kinase p38 and by tristetraprolin itself. J Biol Chem. 2004[PubMed][Google Scholar]
26. Brooks SA, Connolly JE, Rigby WFThe Role of mRNA Turnover in the Regulation of Tristetraprolin Expression: Evidence for an Extracellular Signal-Regulated Kinase-Specific, AU-Rich Element-Dependent, Autoregulatory Pathway. J Immunol. 2004;172:7263–7271.[PubMed][Google Scholar]
27. Stoecklin G, Stubbs T, Kedersha N, Wax S, Rigby WF, Blackwell TK, Anderson PMK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association and ARE-mRNA decay. Embo J. 2004;23:1313–1324.[Google Scholar]
28. Chrestensen CA, Schroeder MJ, Shabanowitz J, Hunt DF, Pelo JW, Worthington MT, Sturgill TWMAPKAP kinase 2 phosphorylates tristetraprolin on in vivo sites including Ser178, a site required for 14-3-3 binding. J Biol Chem. 2004;279:10176–10184.[PubMed][Google Scholar]
29. Rigby WF, Roy K, Collins J, Rigby S, Connolly JE, Bloch DB, Brooks SAStructure/Function Analysis of Tristetraprolin (TTP): p38 Stress-Activated Protein Kinase and Lipopolysaccharide Stimulation Do Not Alter TTP Function. J Immunol. 2005;174:7883–7893.[PubMed][Google Scholar]
30. Kovarik P, Mangold M, Ramsauer K, Heidari H, Steinborn R, Zotter A, Levy DE, Muller M, Decker TSpecificity of signaling by STAT1 depends on SH2 and C-terminal domains that regulate Ser727 phosphorylation, differentially affecting specific target gene expression. Embo J. 2001;20:91–100.[Google Scholar]
31. Baccarini M, Bistoni F, Lohmann-Matthes MLIn vitro natural cell-mediated cytotoxicity against Candida albicans: macrophage precursors as effector cells. J Immunol. 1985;134:2658–2665.[PubMed][Google Scholar]
32. Durbin JE, Hackenmiller R, Simon MC, Levy DETargeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell. 1996;84:443–450.[PubMed][Google Scholar]
33. Morgan C, Pollard JW, Stanley ERIsolation and characterization of a cloned growth factor dependent macrophage cell line, BAC1.2F5. J Cell Physiol. 1987;130:420–427.[PubMed][Google Scholar]
34. Sambrook J, Fritsch EF, Maniatis T Molecular cloning: A laboratory manual. Cold Spring Harbor Laboratory Press; 1989. [PubMed][Google Scholar]
35. Kovarik P, Stoiber D, Novy M, Decker TStat1 combines signals derived from IFN-gamma and LPS receptors during macrophage activation. Embo J. 1998;17:3660–3668. published erratum appears in EMBO J 1998 Jul 15;17(14):4210. [Google Scholar]
36. Morrison TB, Weis JJ, Wittwer CTQuantification of low-copy transcripts by continuous SYBR Green I monitoring during amplification. Biotechniques. 1998;24:954–958. 960, 962.[PubMed][Google Scholar]
37. Groudine M, Peretz M, Weintraub HTranscriptional regulation of hemoglobin switching in chicken embryos. Mol Cell Biol. 1981;1:281–288.[Google Scholar]
38. Porras A, Zuluaga S, Black E, Valladares A, Alvarez AM, Ambrosino C, Benito M, Nebreda ARP38 alpha mitogen-activated protein kinase sensitizes cells to apoptosis induced by different stimuli. Mol Biol Cell. 2004;15:922–933.[Google Scholar]
39. Fukunaga R, Hunter TMNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. Embo J. 1997;16:1921–1933.[Google Scholar]
40. Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe AS, Kaplan DH, Riley JK, Greenlund AC, Campbell D, Carver-Moore K, DuBois RN, Clark R, Aguet M, Schreiber RDTargeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell. 1996;84:431–442.[PubMed][Google Scholar]
41. Rousseau S, Morrice N, Peggie M, Campbell DG, Gaestel M, Cohen PInhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by MAPKAP-K2 and its interaction with cytokine mRNAs. Embo J. 2002;21:6505–6514.[Google Scholar]
42. Decker T, Kovarik P, Meinke AGAS elements: a few nucleotides with a major impact on cytokine-induced gene expression. J Interferon Cytokine Res. 1997;17:121–134.[PubMed][Google Scholar]
43. Chen ZY, Shie JL, Tseng CCSTAT1 is required for IFN-gamma-mediated gut-enriched Kruppel-like factor expression. Exp Cell Res. 2002;281:19–27.[PubMed][Google Scholar]
44. Gao J, Morrison DC, Parmely TJ, Russell SW, Murphy WJAn interferon-gamma-activated site (GAS) is necessary for full expression of the mouse iNOS gene in response to interferon-gamma and lipopolysaccharide. J Biol Chem. 1997;272:1226–1230.[PubMed][Google Scholar]
45. Gao JJ, Filla MB, Fultz MJ, Vogel SN, Russell SW, Murphy WJAutocrine/paracrine IFN-alphabeta mediates the lipopolysaccharide-induced activation of transcription factor Stat1alpha in mouse macrophages: pivotal role of Stat1alpha in induction of the inducible nitric oxide synthase gene. J Immunol. 1998;161:4803–4810.[PubMed][Google Scholar]
46. Sing A, Merlin T, Knopf HP, Nielsen PJ, Loppnow H, Galanos C, Freudenberg MABacterial induction of beta interferon in mice is a function of the lipopolysaccharide component. Infect Immun. 2000;68:1600–1607.[Google Scholar]
47. Toshchakov V, Jones BW, Perera PY, Thomas K, Cody MJ, Zhang S, Williams BR, Major J, Hamilton TA, Fenton MJ, Vogel SNTLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. Nat Immunol. 2002;3:392–398.[PubMed][Google Scholar]
48. Lai WS, Carballo E, Strum JR, Kennington EA, Phillips RS, Blackshear PJEvidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor alpha mRNA. Mol Cell Biol. 1999;19:4311–4323.[Google Scholar]
49. Bakheet T, Williams BR, Khabar KSARED 2.0: an update of AU-rich element mRNA database. Nucleic Acids Res. 2003;31:421–423.[Google Scholar]
50. Alexander WS, Hilton DJThe role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Annu Rev Immunol. 2004;22:503–529.[PubMed][Google Scholar]
51. English J, Pearson G, Wilsbacher J, Swantek J, Karandikar M, Xu S, Cobb MHNew insights into the control of MAP kinase pathways. Exp Cell Res. 1999;253:255–270.[PubMed][Google Scholar]
52. Schleicher U, Hesse A, Bogdan CMinute numbers of contaminant CD8+ T cells or CD11b+CD11c+ NK cells are the source of IFN-gamma in IL-12/IL-18-stimulated mouse macrophage populations. Blood. 2005;105:1319–1328.[PubMed][Google Scholar]
53. Marie I, Durbin JE, Levy DEDifferential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7. Embo J. 1998;17:6660–6669.[Google Scholar]
54. Stockinger S, Reutterer B, Schaljo B, Schellack C, Brunner S, Materna T, Yamamoto M, Akira S, Taniguchi T, Murray PJ, Muller M, Decker TIFN regulatory factor 3-dependent induction of type I IFNs by intracellular bacteria is mediated by a TLR- and Nod2-independent mechanism. J Immunol. 2004;173:7416–7425.[PubMed][Google Scholar]
55. de Veer MJ, Holko M, Frevel M, Walker E, Der S, Paranjape JM, Silverman RH, Williams BRFunctional classification of interferon-stimulated genes identified using microarrays. J Leukoc Biol. 2001;69:912–920.[PubMed][Google Scholar]