Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Regulation of type I interferon responses

Key Points

  • Type I interferon (IFN) responses are regulated by host, pathogen and environmental factors. These factors calibrate the host defences while limiting tissue damage and preventing autoimmunity.

  • Type I IFNs signal via the IFNα receptor (IFNAR) to activate receptor-associated Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2) kinases and downstream signal transducer and activator of transcription (STAT) transcription factors; these transcription factors then induce the expression of IFN-stimulated genes (ISGs). Type I IFNs activate the IFN-stimulated gene factor 3 (ISGF3) complex, which is comprised of STAT1, STAT2 and IFN-regulatory factor 9 (IRF9); the ISGF3 complex binds to IFN-stimulated response elements (ISREs) to induce the expression of antiviral genes.

  • Type I IFN signalling is regulated in a quantitative and qualitative manner. The magnitude of signalling is increased by induction of STAT1 and IRF9 expression and amplification of JAK signalling by spleen tyrosine kinase (SYK) and protein tyrosine kinase 2 (PYK2). Conversely, the magnitude of signalling is decreased by suppressor of cytokine signalling (SOCS) and ubiquitin carboxy-terminal hydrolase 18 (USP18) proteins and by the downregulation and internalization of IFNAR. The qualitative nature of type I IFN responses is determined by the balance between the activation of various STATs and ISGF3.

  • Type I IFN-induced transcription is regulated by the post-translational modification of STATs, chromatin remodelling, the epigenetic landscape and cooperation with other transcription factors, co-activators and co-repressors.

  • ISGs encode proteins that regulate the translation of IFNAR and JAK–STAT signalling components and of ISGs themselves. Type I IFNs also induce the expression of microRNAs that regulate the IFN response.

  • Chronic type I IFN responses can promote autoimmunity by increasing antigen presentation, lymphocyte-mediated adaptive immune responses and chemokine expression. In chronic infections, type I IFNs can induce immunosuppression in part by increasing expression of interleukin-10 and programmed cell death 1 ligand 1 (PDL1).

Abstract

Type I interferons (IFNs) activate intracellular antimicrobial programmes and influence the development of innate and adaptive immune responses. Canonical type I IFN signalling activates the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway, leading to transcription of IFN-stimulated genes (ISGs). Host, pathogen and environmental factors regulate the responses of cells to this signalling pathway and thus calibrate host defences while limiting tissue damage and preventing autoimmunity. Here, we summarize the signalling and epigenetic mechanisms that regulate type I IFN-induced STAT activation and ISG transcription and translation. These regulatory mechanisms determine the biological outcomes of type I IFN responses and whether pathogens are cleared effectively or chronic infection or autoimmune disease ensues.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Type I interferon controls innate and adaptive immunity and intracellular antimicrobial programmes.
Figure 2: The canonical type I interferon signalling pathway.
Figure 3: Type I interferon signalling is regulated by heterologous pathways.
Figure 4: Type I interferon induction of interferon-stimulated genes involves chromatin remodelling and recruitment of various transcriptional activators.
Figure 5: Persistent type I interferon exposure in autoimmune disease and chronic infection induces immunosuppressive pathways.

Similar content being viewed by others

References

  1. Trinchieri, G. Type I interferon: friend or foe? J. Exp. Med. 207, 2053–2063 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Pestka, S., Krause, C. D. & Walter, M. R. Interferons, interferon-like cytokines, and their receptors. Immunol. Rev. 202, 8–32 (2004).

    CAS  PubMed  Google Scholar 

  3. Hertzog, P. J. & Williams, B. R. Fine tuning type I interferon responses. Cytokine Growth Factor Rev. 24, 217–225 (2013).

    CAS  PubMed  Google Scholar 

  4. Paludan, S. R. & Bowie, A. G. Immune sensing of DNA. Immunity 38, 870–880 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Goubau, D., Deddouche, S. & Reis, E. S. C. Cytosolic sensing of viruses. Immunity 38, 855–869 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Iwasaki, A. A virological view of innate immune recognition. Annu. Rev. Microbiol. 66, 177–196 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Levy, D. E. & Darnell, J. E. Jr. STATs: transcriptional control and biological impact. Nature Rev. Mol. Cell Biol. 3, 651–662 (2002).

    CAS  Google Scholar 

  8. Stark, G. R. & Darnell, J. E. Jr. The JAK-STAT pathway at twenty. Immunity 36, 503–514 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. MacMicking, J. D. Interferon-inducible effector mechanisms in cell-autonomous immunity. Nature Rev. Immunol. 12, 367–382 (2012).

    CAS  Google Scholar 

  10. Schoggins, J. W. et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472, 481–485 (2011). This study identifies specific antiviral functions for multiple ISGs, showing that unique sets of ISGs target distinct viruses. It highlights the importance of translational regulation.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Rusinova, I. et al. Interferome v2.0: an updated database of annotated interferon-regulated genes. Nucleic Acids Res. 41, D1040–D1046 (2012).

    PubMed  PubMed Central  Google Scholar 

  12. Saka, H. A. & Valdivia, R. Emerging roles for lipid droplets in immunity and host-pathogen interactions. Annu. Rev. Cell Dev. Biol. 28, 411–437 (2012).

    CAS  PubMed  Google Scholar 

  13. van Boxel-Dezaire, A. H., Rani, M. R. & Stark, G. R. Complex modulation of cell type-specific signaling in response to type I interferons. Immunity 25, 361–372 (2006).

    CAS  PubMed  Google Scholar 

  14. Gough, D. J., Messina, N. L., Clarke, C. J., Johnstone, R. W. & Levy, D. E. Constitutive type I interferon modulates homeostatic balance through tonic signaling. Immunity 36, 166–174 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Abt, M. C. et al. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity 37, 158–170 (2012). Together with references 16 and 17, this study demonstrates that the commensal microflora calibrates innate immune responses and maintains homeostasis in part by providing tonic signals that maintain a basal systemic IFN response.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Ganal, S. C. et al. Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota. Immunity 37, 171–186 (2012).

    CAS  PubMed  Google Scholar 

  17. Kawashima, T. et al. Double-stranded RNA of intestinal commensal but not pathogenic bacteria triggers production of protective interferon-β. Immunity 38, 1187–1197 (2013).

    CAS  PubMed  Google Scholar 

  18. Wang, L. et al. 'Tuning' of type I interferon-induced Jak-STAT1 signaling by calcium-dependent kinases in macrophages. Nature Immunol. 9, 186–193 (2008). This study demonstrates cross-regulation of type I IFN signalling by ITAM-associated receptors, with resultant fine-tuning of ISG induction.

    CAS  Google Scholar 

  19. Gilchrist, D. A. et al. Regulating the regulators: the pervasive effects of Pol II pausing on stimulus-responsive gene networks. Genes Dev. 26, 933–944 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Papadopoulou, A. S. et al. The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-α receptor. Nature Immunol. 13, 181–187 (2012).

    CAS  Google Scholar 

  21. Lu, L. F. et al. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142, 914–929 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Gracias, D. T. et al. The microRNA miR-155 controls CD8+ T cell responses by regulating interferon signaling. Nature Immunol. 14, 593–602 (2013). This study establishes that miRNAs regulate type I IFN responses by demonstrating that miR-155 targets IFN signalling components.

    CAS  Google Scholar 

  23. David, M. Interferons and microRNAs. J. Interferon Cytokine Res. 30, 825–828 (2010).

    CAS  PubMed  Google Scholar 

  24. Levy, D. E., Lew, D. J., Decker, T., Kessler, D. S. & Darnell, J. E. Jr. Synergistic interaction between interferon-α and interferon-γ through induced synthesis of one subunit of the transcription factor ISGF3. EMBO J. 9, 1105–1111 (1990). Together with reference 25, this study demonstrates that the priming of augmented IFN responses is mediated by increased expression of IRF9 and STAT1.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hu, X. et al. Sensitization of IFN-γ Jak-STAT signaling during macrophage activation. Nature Immunol. 3, 859–866 (2002).

    CAS  Google Scholar 

  26. Tassiulas, I. et al. Amplification of IFN-α-induced STAT1 activation and inflammatory function by Syk and ITAM-containing adaptors. Nature Immunol. 5, 1181–1189 (2004).

    CAS  Google Scholar 

  27. Hu, X., Park-Min, K. H., Ho, H. H. & Ivashkiv, L. B. IFN-γ-primed macrophages exhibit increased CCR2-dependent migration and altered IFN-γ responses mediated by Stat1. J. Immunol. 175, 3637–3647 (2005).

    CAS  PubMed  Google Scholar 

  28. Yarilina, A., Park-Min, K.-H., Antoniv, T., Hu, X. & Ivashkiv, L. B. TNF activates an IRF1-dependent autocrine loop leading to sustained expression of chemokines and STAT1-dependent type I interferon-response genes. Nature Immunol. 9, 378–387 (2008).

    CAS  Google Scholar 

  29. Venkatesh, D. et al. Endothelial TNF receptor 2 induces IRF1 transcription factor-dependent interferon-beta autocrine signaling to promote monocyte recruitment. Immunity 38, 1025–1037 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Cheon, H. et al. IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage. EMBO J. 32, 2751–2763 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Fuchs, S. Y. Hope and fear for interferon: the receptor-centric outlook on the future of interferon therapy. J. Interferon Cytokine Res. 33, 211–225 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. de Weerd, N. A. & Nguyen, T. The interferons and their receptors--distribution and regulation. Immunol. Cell Biol. 90, 483–491 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Bhattacharya, S. et al. Anti-tumorigenic effects of Type 1 interferon are subdued by integrated stress responses. Oncogene 32, 4214–4221 (2013).

    CAS  PubMed  Google Scholar 

  34. Huynh, L., Wang, L., Shi, C., Park-Min, K. H. & Ivashkiv, L. B. ITAM-coupled receptors inhibit IFNAR signaling and alter macrophage responses to TLR4 and Listeria monocytogenes. J. Immunol. 188, 3447–3457 (2012).

    CAS  PubMed  Google Scholar 

  35. Huangfu, W.-C. et al. Inflammatory signaling compromises cell responses to interferon alpha. Oncogene 31, 161–172 (2011).

    PubMed  PubMed Central  Google Scholar 

  36. Liu, J. et al. Virus-induced unfolded protein response attenuates antiviral defenses via phosphorylation-dependent degradation of the type I interferon receptor. Cell Host Microbe 5, 72–83 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang, L. et al. Indirect inhibition of Toll-like receptor and type I interferon responses by ITAM-coupled receptors and integrins. Immunity 32, 518–530 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Du, Z. et al. Inhibition of IFN-α signaling by a PKC- and protein tyrosine phosphatase SHP-2-dependent pathway. Proc. Natl Acad. Sci. USA 102, 10267–10272 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Yoshimura, A., Naka, T. & Kubo, M. SOCS proteins, cytokine signalling and immune regulation. Nature Rev. Immunol. 7, 454–465 (2007).

    CAS  Google Scholar 

  40. Sarasin-Filipowicz, M. et al. Alpha interferon induces long-lasting refractoriness of JAK-STAT signaling in the mouse liver through induction of USP18/UBP43. Mol. Cell. Biol. 29, 4841–4851 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Nazarov, P. V. et al. Interplay of microRNAs, transcription factors and target genes: linking dynamic expression changes to function. Nucleic Acids Res. 41, 2817–2831 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Tili, E. et al. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-α stimulation and their possible roles in regulating the response to endotoxin shock. J. Immunol. 179, 5082–5089 (2007).

    CAS  PubMed  Google Scholar 

  43. Murray, P. J. The JAK-STAT signaling pathway: input and output integration. J. Immunol. 178, 2623–2629 (2007).

    CAS  PubMed  Google Scholar 

  44. Ho, H. H. & Ivashkiv, L. B. Role of STAT3 in type I interferon responses. Negative regulation of STAT1-dependent inflammatory gene activation. J. Biol. Chem. 281, 14111–14118 (2006).

    CAS  PubMed  Google Scholar 

  45. Wang, W. B., Levy, D. E. & Lee, C. K. STAT3 negatively regulates type I IFN-mediated antiviral response. J. Immunol. 187, 2578–2585 (2011).

    CAS  PubMed  Google Scholar 

  46. Nguyen, K. B. et al. Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection. Science 297, 2063–2066 (2002). This study demonstrates a switch in type I IFN signalling from STAT1 to STAT4 that shapes CD8+ T cell responses during viral infection in vivo.

    CAS  PubMed  Google Scholar 

  47. Gil, M. P. et al. Regulating type 1 IFN effects in CD8 T cells during viral infections: changing STAT4 and STAT1 expression for function. Blood 120, 3718–3728 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Tenoever, B. R. et al. Multiple functions of the IKK-related kinase IKKε in interferon-mediated antiviral immunity. Science 315, 1274–1278 (2007).

    CAS  PubMed  Google Scholar 

  49. Ng, S. L. et al. IkappaB kinase epsilon (IKKε) regulates the balance between type I and type II interferon responses. Proc. Natl Acad. Sci. USA 108, 21170–21175 (2012).

    Google Scholar 

  50. Robinson, N. et al. Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium. Nature Immunol. 13, 954–962 (2012).

    CAS  Google Scholar 

  51. de Weerd, N. A. et al. Structural basis of a unique interferon-β signaling axis mediated via the receptor IFNAR1. Nature Immunol. 14, 901–907 (2013).

    CAS  Google Scholar 

  52. Sadzak, I. et al. Recruitment of Stat1 to chromatin is required for interferon-induced serine phosphorylation of Stat1 transactivation domain. Proc. Natl Acad. Sci. USA 105, 8944–8949 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Bancerek, J. et al. CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response. Immunity 38, 250–262 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Yang, J. et al. Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes. Proc. Natl Acad. Sci. USA 107, 21499–21504 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Droescher, M., Begitt, A., Marg, A., Zacharias, M. & Vinkemeier, U. Cytokine-induced paracrystals prolong the activity of signal transducers and activators of transcription (STAT) and provide a model for the regulation of protein solubility by small ubiquitin-like modifier (SUMO). J. Biol. Chem. 286, 18731–18746 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Hu, X. & Ivashkiv, L. B. Cross-regulation of signaling pathways by interferon-γ: implications for immune responses and autoimmune diseases. Immunity 31, 539–550 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Tamura, T., Yanai, H., Savitsky, D. & Taniguchi, T. The IRF family transcription factors in immunity and oncogenesis. Annu. Rev. Immunol. 26, 535–584 (2008).

    CAS  PubMed  Google Scholar 

  58. Levy, D. E., Marie, I., Smith, E. & Prakash, A. Enhancement and diversification of IFN induction by IRF-7-mediated positive feedback. J. Interferon Cytokine Res. 22, 87–93 (2002).

    CAS  PubMed  Google Scholar 

  59. Farlik, M. et al. Contribution of a TANK-binding kinase 1-interferon (IFN) regulatory factor 7 pathway to IFN-γ-induced gene expression. Mol. Cell. Biol. 32, 1032–1043 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Qiao, Y. et al. Synergistic activation of inflammatory cytokine genes by interferon-γ-induced chromatin remodeling and Toll-like receptor signaling. Immunity 39, 454–469 (2013). Together with references 79 and 80, this study demonstrates a pervasive binding of STAT1 to promoters and enhancers genome-wide that programs cellular responses to environmental cues.

    CAS  PubMed  Google Scholar 

  61. Chatterjee-Kishore, M., Wright, K. L., Ting, J. P. & Stark, G. R. How Stat1 mediates constitutive gene expression: a complex of unphosphorylated Stat1 and IRF1 supports transcription of the LMP2 gene. EMBO J. 19, 4111–4122 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Farlik, M. et al. Nonconventional initiation complex assembly by STAT and NF-κB transcription factors regulates nitric oxide synthase expression. Immunity 33, 25–34 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Xu, D. et al. Promyelocytic leukemia zinc finger protein regulates interferon-mediated innate immunity. Immunity 30, 802–816 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Litvak, V. et al. A FOXO3-IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses. Nature 490, 421–425 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Shalek, A. K. et al. Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells. Nature 498, 236–240 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhao, M., Zhang, J., Phatnani, H., Scheu, S. & Maniatis, T. Stochastic expression of the interferon-beta gene. PLoS Biol. 10, e1001249 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Hwang, S. Y. et al. Biphasic RLR-IFN-β response controls the balance between antiviral immunity and cell damage. J. Immunol. 190, 1192–1200 (2013).

    CAS  PubMed  Google Scholar 

  68. Bell, O., Tiwari, V. K., Thoma, N. H. & Schubeler, D. Determinants and dynamics of genome accessibility. Nature Rev. Genet. 12, 554–564 (2011).

    CAS  PubMed  Google Scholar 

  69. Smale, S. T. Selective transcription in response to an inflammatory stimulus. Cell 140, 833–844 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Yan, Z. et al. PBAF chromatin-remodeling complex requires a novel specificity subunit, BAF200, to regulate expression of selective interferon-responsive genes. Genes Dev. 19, 1662–1667 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Liu, H., Kang, H., Liu, R., Chen, X. & Zhao, K. Maximal induction of a subset of interferon target genes requires the chromatin-remodeling activity of the BAF complex. Mol. Cell. Biol. 22, 6471–6479 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Cui, K. et al. The chromatin-remodeling BAF complex mediates cellular antiviral activities by promoter priming. Mol. Cell. Biol. 24, 4476–4486 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Huang, M. et al. Chromatin-remodelling factor BRG1 selectively activates a subset of interferon-α-inducible genes. Nature Cell Biol. 4, 774–781 (2002).

    CAS  PubMed  Google Scholar 

  74. Ni, Z. et al. Apical role for BRG1 in cytokine-induced promoter assembly. Proc. Natl Acad. Sci. USA 102, 14611–14616 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Ramirez-Carrozzi, V. R. et al. Selective and antagonistic functions of SWI/SNF and Mi-2β nucleosome remodeling complexes during an inflammatory response. Genes Dev. 20, 282–296 (2006). This study establishes the importance of chromatin remodelling for the induction of inflammatory genes and ISGs.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Ramirez-Carrozzi, V. R. et al. A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling. Cell 138, 114–128 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Bhatt, D. M. et al. Transcript dynamics of proinflammatory genes revealed by sequence analysis of subcellular RNA fractions. Cell 150, 279–290 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Zentner, G. E. & Henikoff, S. Regulation of nucleosome dynamics by histone modifications. Nature Struct. Mol. Biol. 20, 259–266 (2013).

    CAS  Google Scholar 

  79. Vahedi, G. et al. STATs shape the active enhancer landscape of T cell populations. Cell 151, 981–993 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Ostuni, R. et al. Latent enhancers activated by stimulation in differentiated cells. Cell 152, 157–171 (2013).

    CAS  PubMed  Google Scholar 

  81. Hargreaves, D. C., Horng, T. & Medzhitov, R. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138, 129–145 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Nicodeme, E. et al. Suppression of inflammation by a synthetic histone mimic. Nature 468, 1119–1123 (2010). This study demonstrates the feasibility of therapeutic targeting of chromatin regulatory proteins to selectively suppress inflammatory gene and ISG expression.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Patel, M. C. et al. BRD4 coordinates recruitment of pause release factor P-TEFb and the pausing complex NELF/DSIF to regulate transcription elongation of interferon-stimulated genes. Mol. Cell. Biol. 33, 2497–2507 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Shakespear, M. R., Halili, M. A., Irvine, K. M., Fairlie, D. P. & Sweet, M. J. Histone deacetylases as regulators of inflammation and immunity. Trends Immunol. 32, 335–343 (2011).

    CAS  PubMed  Google Scholar 

  85. Fonseca, G. J. et al. Adenovirus evasion of interferon-mediated innate immunity by direct antagonism of a cellular histone posttranslational modification. Cell Host Microbe 11, 597–606 (2012).

    CAS  PubMed  Google Scholar 

  86. Lau, J. F., Nusinzon, I., Burakov, D., Freedman, L. P. & Horvath, C. M. Role of metazoan mediator proteins in interferon-responsive transcription. Mol. Cell. Biol. 23, 620–628 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Gnatovskiy, L., Mita, P. & Levy, D. E. The human RVB complex is required for efficient transcription of type I IFN-stimulated genes. Mol Cell. Biol. 33, 3817–3825 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Flammer, J. R. et al. The type I interferon signaling pathway is a target for glucocorticoid inhibition. Mol. Cell. Biol. 30, 4564–4574 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Icardi, L. et al. The Sin3a repressor complex is a master regulator of STAT transcriptional activity. Proc. Natl Acad. Sci. USA 109, 12058–12063 (2012). This study reveals the association of co-repressors with specific STATs as a mechanism that can selectively silence the expression of subsets of type I IFN response genes.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Tahk, S. et al. Control of specificity and magnitude of NF-κB and STAT1-mediated gene activation through PIASy and PIAS1 cooperation. Proc. Natl Acad. Sci. USA 104, 11643–11648 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Shuai, K. & Liu, B. Regulation of gene-activation pathways by PIAS proteins in the immune system. Nature Rev. Immunol. 5, 593–605 (2005).

    CAS  Google Scholar 

  92. Liu, B., Tahk, S., Yee, K. M., Fan, G. & Shuai, K. The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression. Science 330, 521–525 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Marazzi, I. et al. Suppression of the antiviral response by an influenza histone mimic. Nature 483, 428–433 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Natoli, G., Ghisletti, S. & Barozzi, I. The genomic landscapes of inflammation. Genes Dev. 25, 101–106 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Fang, T. C. et al. Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response. J. Exp. Med. 209, 661–669 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Ea, C. K., Hao, S., Yeo, K. S. & Baltimore, D. EHMT1 protein binds to nuclear factor-κB p50 and represses gene expression. J. Biol. Chem. 287, 31207–31217 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Walsh, D., Mathews, M. B. & Mohr, I. Tinkering with translation: protein synthesis in virus-infected cells. Cold Spring Harb. Perspect. Biol. 5, a012351 (2013).

    PubMed  PubMed Central  Google Scholar 

  98. Kaur, S. et al. Regulatory effects of mTORC2 complexes in type I IFN signaling and in the generation of IFN responses. Proc. Natl Acad. Sci. USA 109, 7723–7728 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Kaur, S. et al. Role of the Akt pathway in mRNA translation of interferon-stimulated genes. Proc. Natl Acad. Sci. USA 105, 4808–4813 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Joshi, S., Kaur, S., Kroczynska, B. & Platanias, L. C. Mechanisms of mRNA translation of interferon stimulated genes. Cytokine 52, 123–127 (2010).

    CAS  PubMed  Google Scholar 

  101. Rani, M. R., Hibbert, L., Sizemore, N., Stark, G. R. & Ransohoff, R. M. Requirement of phosphoinositide 3-kinase and Akt for interferon-β-mediated induction of the beta-R1 (SCYB11) gene. J. Biol. Chem. 277, 38456–38461 (2002).

    CAS  PubMed  Google Scholar 

  102. Thoreen, C. C. et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485, 109–113 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Hsieh, A. C. et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485, 55–61 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Colina, R. et al. Translational control of the innate immune response through IRF-7. Nature 452, 323–328 (2008).

    CAS  PubMed  Google Scholar 

  105. Ruggieri, A. et al. Dynamic oscillation of translation and stress granule formation mark the cellular response to virus infection. Cell Host Microbe 12, 71–85 (2012).

    CAS  PubMed  Google Scholar 

  106. Terenzi, F., Hui, D. J., Merrick, W. C. & Sen, G. C. Distinct induction patterns and functions of two closely related interferon-inducible human genes, ISG54 and ISG56. J. Biol. Chem. 281, 34064–34071 (2006).

    CAS  PubMed  Google Scholar 

  107. Fensterl, V. & Sen, G. C. The ISG56/IFIT1 gene family. J. Interferon Cytokine Res. 31, 71–78 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Lee, M. S., Kim, B., Oh, G. T. & Kim, Y. J. OASL1 inhibits translation of the type I interferon-regulating transcription factor IRF7. Nature Immunol. 14, 346–355 (2013).

    CAS  Google Scholar 

  109. Hall, J. C. & Rosen, A. Type I interferons: crucial participants in disease amplification in autoimmunity. Nature Rev. Rheumatol. 6, 40–49 (2010).

    CAS  Google Scholar 

  110. Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Rai, E. & Wakeland, E. K. Genetic predisposition to autoimmunity—what have we learned? Semin. Immunol. 23, 67–83 (2011).

    CAS  PubMed  Google Scholar 

  112. Forster, S. Interferon signatures in immune disorders and disease. Immunol. Cell Biol. 90, 520–527 (2012).

    CAS  PubMed  Google Scholar 

  113. Teles, R. M. B. et al. Type I interferon suppresses type II interferon-triggered human anti-mycobacterial responses. Science 339, 1448–1453 (2013). Together with references 114–116 and 124–127, this study demonstrates a dominant suppressive function of type I IFNs in chronic infections that is mediated by the induction of IL-10 and PDL1.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Berry, M. P. et al. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature 466, 973–977 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. McNab, F. W. et al. TPL-2-ERK1/2 signaling promotes host resistance against intracellular bacterial infection by negative regulation of type I IFN production. J. Immunol. 191, 1732–1743 (2013).

    CAS  PubMed  Google Scholar 

  116. O'Garra, A. et al. The immune response in tuberculosis. Annu. Rev. Immunol. 31, 475–527 (2013).

    CAS  PubMed  Google Scholar 

  117. Kalliolias, G. D. & Ivashkiv, L. B. Overview of the biology of type I interferons. Arthritis Res. Ther. 12 (Suppl. 1), S1 (2010).

    PubMed  PubMed Central  Google Scholar 

  118. Ivashkiv, L. B. PTPN22 in autoimmunity: different cell and different way. Immunity 39, 91–93 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Wang, Y. et al. The autoimmunity-associated gene PTPN22 potentiates toll-like receptor-driven, type 1 interferon-dependent immunity. Immunity 39, 111–122 (2013).

    CAS  PubMed  Google Scholar 

  120. Prinz, M. et al. Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 28, 675–686 (2008).

    CAS  PubMed  Google Scholar 

  121. Cantaert, T., Baeten, D., Tak, P. P. & van Baarsen, L. G. Type I IFN and TNFalpha cross-regulation in immune- mediated inflammatory disease: basic concepts and clinical relevance. Arthritis Res. Ther. 12, 219 (2010).

    PubMed  PubMed Central  Google Scholar 

  122. Banchereau, J., Pascual, V. & Palucka, A. K. Autoimmunity through cytokine-induced dendritic cell activation. Immunity 20, 539–550 (2004).

    CAS  PubMed  Google Scholar 

  123. Gordon, R. A., Grigoriev, G., Lee, A., Kalliolias, G. D. & Ivashkiv, L. B. The interferon signature and STAT1 expression in rheumatoid arthritis synovial fluid macrophages are induced by tumor necrosis factor alpha and counter-regulated by the synovial fluid microenvironment. Arthritis Rheum. 64, 3119–3128 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Wilson, E. B. et al. Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science 340, 202–207 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Teijaro, J. R. et al. Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science 340, 207–211 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Antonelli, L. R. et al. Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population. J. Clin. Invest. 120, 1674–1682 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Mayer-Barber, K. D. et al. Innate and adaptive interferons suppress IL-1α and IL-1β production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection. Immunity 35, 1023–1034 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Su, A. I. et al. Genomic analysis of the host response to hepatitis C virus infection. Proc. Natl Acad. Sci. USA 99, 15669–15674 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Guidotti, L. G. & Chisari, F. V. Immunobiology and pathogenesis of viral hepatitis. Annu. Rev. Pathol. 1, 23–61 (2006).

    CAS  PubMed  Google Scholar 

  130. Kulpa, D. A. et al. PD-1 coinhibitory signals: the link between pathogenesis and protection. Semin. Immunol. 25, 219–227 (2013).

    CAS  PubMed  Google Scholar 

  131. Hajishengallis, G. & Lambris, J. D. Microbial manipulation of receptor crosstalk in innate immunity. Nature Rev. Immunol. 11, 187–200 (2011).

    CAS  Google Scholar 

  132. Maecker, H. T., McCoy, J. P. & Nussenblatt, R. Standardizing immunophenotyping for the Human Immunology Project. Nature Rev. Immunol. 12, 191–200 (2012).

    CAS  Google Scholar 

  133. Davis, M. M. Immunology taught by humans. Sci Transl. Med. 4, 117fs2 (2012).

    PubMed  PubMed Central  Google Scholar 

  134. Fung, K. Y. et al. Interferon-ε protects the female reproductive tract from viral and bacterial infection. Science 339, 1088–1092 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Wang, H. et al. The role of glycogen synthase kinase 3 in regulating IFN-β-mediated IL-10 production. J. Immunol. 186, 675–684 (2011).

    CAS  PubMed  Google Scholar 

  136. Chen, X. et al. Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages. Proc. Natl Acad. Sci. USA 109, E2865–E2874 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Khabar, K. S. & Young, H. A. Post-transcriptional control of the interferon system. Biochimie 89, 761–769 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Schulz, O. et al. Protein kinase R contributes to immunity against specific viruses by regulating interferon mRNA integrity. Cell Host Microbe 7, 354–361 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank P. Crow for critical review of the manuscript. This work was supported by grants from the US National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lionel B. Ivashkiv.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

MicroRNAs

(miRNAs). Small RNA molecules that regulate the expression of genes by binding to the 3′ untranslated regions of specific mRNAs.

Degron sequence

Degrons are signals within proteins that target them for rapid degradation. Degrons can be overt, as in the case of the N-end rule, or covert, as in the case of cyclins. For example, cyclin B must be rapidly destroyed after mitosis, and this is achieved by kinase-regulated access to a 'destruction box' sequence in cyclin B that stimulates polyubiquitylation and subsequent degradation by the proteasome.

Mediator

A multiprotein complex that functions as a co-activator of transcription in all eukaryotes.

Sumoylated

A sumoylated protein has undergone a type of post-translational protein modification in which the ubiquitin-like protein SUMO (small ubiquitin-related modifier) is covalently attached to the protein by an enzymatic cascade that is analogous to the cascade involved in protein ubiquitylation.

CpG islands

Sequences of 0.5–2 kilobases that are rich in CpG dinucleotides. They are mostly located upstream of housekeeping genes and also of some tissue-specific genes. They are constitutively hypomethylated in many animal cell types.

RVB proteins

ATP-binding proteins that belong to the ATPase- associated with diverse cellular activities (AAA) family of ATPases. They are found in different protein and nucleoprotein complexes that have roles in diverse cellular responses, including transcription, mitosis, development, apoptosis and DNA damage responses.

IFN signature

A pattern of increased expression of interferon- stimulated genes (ISGs) in tissue samples or stimulated cells. The IFN signature is typically detected by using a high-throughput approach, such as microarray or RNA sequencing, to analyse gene expression.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ivashkiv, L., Donlin, L. Regulation of type I interferon responses. Nat Rev Immunol 14, 36–49 (2014). https://doi.org/10.1038/nri3581

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3581

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing