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The adaptor Act1 is required for interleukin 17–dependent signaling associated with autoimmune and inflammatory disease

Nature Immunology volume 8, pages 247–256 (2007)Cite this article

Abstract

T helper cells that produce interleukin 17 (IL-17) are associated with inflammation and the control of certain bacteria. We report here the essential involvement of the adaptor protein Act1 in IL-17 receptor (IL-17R) signaling and IL-17-dependent immune responses. After stimulation with IL-17, recruitment of Act1 to IL-17R required the IL-17R conserved cytoplasmic 'SEFIR' domain, followed by recruitment of the kinase TAK1 and E3 ubiquitin ligase TRAF6, which mediate 'downstream' activation of transcription factor NF-κB. IL-17-induced expression of inflammation-related genes was abolished in Act1-deficient primary astroglial and gut epithelial cells. This reduction was associated with much less inflammatory disease in vivo in both autoimmune encephalomyelitis and dextran sodium sulfate–induced colitis. Our data show that Act1 is essential in IL-17-dependent signaling in autoimmune and inflammatory disease.

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Figure 1: Interaction between Act1 and IL-17R.
Figure 2: Act1 is required for IL-17-mediated expression of inflammation-related genes in MEFs.
Figure 3: IL-17-mediated inflammatory responses are impaired in Act1-deficient mice.
Figure 4: EAE incidence and severity are much lower in Act1-deficient mice.
Figure 5: DSS-induced colitis is lower in mice with epithelial cell–specific Act1 deficiency.
Figure 6: Act1 is required for IL-17-mediated phosphorylation and degradation of IκB.
Figure 7: Components of IL-17 signaling.

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Acknowledgements

We thank R.G. Oshima (Burnham Institute for Medical Research) for K18-Cre mice; D. Cua (DNAX) for technical discussions of T cell transfer experiments; and C. Dong for discussions. Human cortical astrocyte cultures were provided by S. Wright (Elan Pharmaceuticals). Supported by the National Institutes of Health (AI 065470 to X.L.) and the Leukemia and Lymphoma Society (Y.Q.).

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  1. Youcun Qian and Caini Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, Cleveland Clinic, Cleveland, 44195, Ohio, USA

    Youcun Qian, Caini Liu, Justin Hartupee, Cengiz Zubeyir Altuntas, Muhammet Fatih Gulen, Daniel Jane-wit, Jianhua Xiao, Yi Lu, Natalia Giltiay, Qi-Wei Zhang, Vincent K Tuohy, Thomas Hamilton & Xiaoxia Li

  2. Department of Pathology, Case Western Reserve University, Cleveland, 44106, Ohio, USA

    Jinbo Liu

  3. Department of Biochemistry, Virginia Commonwealth University Medical School, Richmond, 23298, Virginia, USA

    Tomasz Kordula

  4. Division of Gastroenterology, University of British Columbia and BC Children's Hospital, Vancouver, V6T 1Z4, British Columbia, Canada

    Bruce Vallance

  5. Department of Pathobiology, Cleveland Clinic Foundation, Cleveland, 44195, Ohio, USA

    Shadi Swaidani & Mark Aronica

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Supplementary information

Supplementary Fig. 1

Model of IL-17 mediated signaling. (PDF 73 kb)

Supplementary Table 1

Primers and oligonucleotides. (PDF 54 kb)

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Qian, Y., Liu, C., Hartupee, J. et al. The adaptor Act1 is required for interleukin 17–dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol 8, 247–256 (2007). https://doi.org/10.1038/ni1439

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