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.

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

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    Kolls, J.K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467–476 (2004).

    CAS  Article  Google Scholar 

  2. 2

    Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

    CAS  Article  Google Scholar 

  3. 3

    Mangan, P.R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    CAS  Article  Google Scholar 

  4. 4

    Harrington, L.E. et al. Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).

    CAS  Article  Google Scholar 

  5. 5

    Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).

    CAS  Article  Google Scholar 

  6. 6

    Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    CAS  Article  Google Scholar 

  7. 7

    Mangan, P.R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    CAS  Article  Google Scholar 

  8. 8

    Nakae, S. et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17, 375–387 (2002).

    CAS  Article  Google Scholar 

  9. 9

    Iwakura, Y. & Ishigame, H. The IL-23/IL-17 axis in inflammation. J. Clin. Invest. 116, 1218–1222 (2006).

    CAS  Article  Google Scholar 

  10. 10

    Kolls, J.K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467–476 (2004).

    CAS  Article  Google Scholar 

  11. 11

    Toy, D. et al. Cutting Edge: Interleukin 17 signals through a heteromeric receptor complex. J. Immunol. 177, 36–39 (2006).

    CAS  Article  Google Scholar 

  12. 12

    Trajkovic, V. et al. Interleukin-17 stimulates inducible nitric oxide synthase activation in rodent astrocytes. J. Neuroimmunol. 119, 183–191 (2001).

    CAS  Article  Google Scholar 

  13. 13

    Inoue, D. et al. IL-17A promotes the growth of airway epithelial cells through ERK-dependent signaling pathway. Biochem. Biophys. Res. Commun. 347, 852–858 (2006).

    CAS  Article  Google Scholar 

  14. 14

    Novatchkova, M., Leibbrandt, A., Werzowa, J., Neubuser, A. & Eisenhaber, F. The STIR-domain superfamily in signal transduction, development and immunity. Trends Biochem. Sci. 28, 226–229 (2003).

    CAS  Article  Google Scholar 

  15. 15

    Yao, Z. et al. Molecular characterization of the human interleukin (IL)-17 receptor. Cytokine 9, 794–800 (1997).

    CAS  Article  Google Scholar 

  16. 16

    Schwandner, R., Yamaguchi, K. & Cao, Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J. Exp. Med. 191, 1233–1240 (2000).

    CAS  Article  Google Scholar 

  17. 17

    Li, X. et al. Act1, an NF-κB-activating protein. Proc. Natl. Acad. Sci. USA 97, 10489–10493 (2000).

    CAS  Article  Google Scholar 

  18. 18

    Leonardi, A., Chariot, A., Claudio, E., Cunningham, K. & Siebenlist, U. CIKS, a connection to IκB kinase and stress-activated protein kinase. Proc. Natl. Acad. Sci. USA 97, 10494–10499 (2000).

    CAS  Article  Google Scholar 

  19. 19

    Qian, Y., Zhao, Z., Jiang, Z. & Li, X. Role of NFκB activator Act1 in CD40-mediated signaling in epithelial cells. Proc. Natl. Acad. Sci. USA 99, 9386–9391 (2002).

    CAS  Article  Google Scholar 

  20. 20

    Qian, Y. et al. Act1, a negative regulator in CD40- and BAFF-mediated B cell survival. Immunity 21, 575–587 (2004).

    CAS  Article  Google Scholar 

  21. 21

    Novatchkova, M., Leibbrandt, A., Werzowa, J., Neubuser, A. & Eisenhaber, F. The STIR-domain superfamily in signal transduction, development and immunity. Trends Biochem. Sci. 28, 226–229 (2003).

    CAS  Article  Google Scholar 

  22. 22

    Cua, D.J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).

    CAS  Article  Google Scholar 

  23. 23

    Chen, Y. et al. Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J. Clin. Invest. 116, 1317–1326 (2006).

    CAS  Article  Google Scholar 

  24. 24

    Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).

    CAS  Article  Google Scholar 

  25. 25

    Chen, Y. et al. Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. J. Biol. Chem. 278, 17036–17043 (2003).

    CAS  Article  Google Scholar 

  26. 26

    Awane, M., Andres, P.G., Li, D.J. & Reinecker, H.C. NF-κB-inducing kinase is a common mediator of IL-17-, TNF-α-, and IL-1β-induced chemokine promoter activation in intestinal epithelial cells. J. Immunol. 162, 5337–5344 (1999).

    CAS  PubMed  Google Scholar 

  27. 27

    Ruddy, M.J. et al. Functional cooperation between interleukin-17 and tumor necrosis factor-α is mediated by CCAAT/enhancer-binding protein family members. J. Biol. Chem. 279, 2559–2567 (2004).

    CAS  Article  Google Scholar 

  28. 28

    Weaver, A. et al. An elevated matrix metalloproteinase (MMP) in an animal model of multiple sclerosis is protective by affecting Th1/Th2 polarization. FASEB J. 19, 1668–1670 (2005).

    CAS  Article  Google Scholar 

  29. 29

    Becher, B., Bechmann, I. & Greter, M. Antigen presentation in autoimmunity and CNS inflammation: how T lymphocytes recognize the brain. J. Mol. Med. 84, 532–543 (2006).

    CAS  Article  Google Scholar 

  30. 30

    Gold, R., Linington, C. & Lassmann, H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129, 1953–1971 (2006).

    Article  Google Scholar 

  31. 31

    Koenders, M.I. et al. Interleukin-17 receptor deficiency results in impaired synovial expression of interleukin-1 and matrix metalloproteinases 3, 9, and 13 and prevents cartilage destruction during chronic reactivated streptococcal cell wall-induced arthritis. Arthritis Rheum. 52, 3239–3247 (2005).

    CAS  Article  Google Scholar 

  32. 32

    Dong, Y. & Benveniste, E.N. Immune function of astrocytes. Glia 36, 180–190 (2001).

    CAS  Article  Google Scholar 

  33. 33

    Iwakura, Y. & Ishigame, H. The IL-23/IL-17 axis in inflammation. J. Clin. Invest. 116, 1218–1222 (2006).

    CAS  Article  Google Scholar 

  34. 34

    Zhang, Z., Zheng, M., Bindas, J., Schwarzenberger, P. & Kolls, J.K. Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm. Bowel Dis. 12, 382–388 (2006).

    Article  Google Scholar 

  35. 35

    Zhao, Z. et al. IFN regulatory factor-1 is required for the up-regulation of the CD40-NF-κB activator 1 axis during airway inflammation. J. Immunol. 170, 5674–5680 (2003).

    CAS  Article  Google Scholar 

  36. 36

    Schwartz, S., Beaulieu, J.F. & Ruemmele, F.M. Interleukin-17 is a potent immuno-modulator and regulator of normal human intestinal epithelial cell growth. Biochem. Biophys. Res. Commun. 337, 505–509 (2005).

    CAS  Article  Google Scholar 

  37. 37

    Wen, F. et al. Expression of conditional cre recombinase in epithelial tissues of transgenic mice. Genesis 35, 100–106 (2003).

    CAS  Article  Google Scholar 

  38. 38

    Kolls, J.K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467–476 (2004).

    CAS  Article  Google Scholar 

  39. 39

    Ye, P. et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med. 194, 519–527 (2001).

    CAS  Article  Google Scholar 

  40. 40

    Kullberg, M.C. et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J. Exp. Med. 203, 2485–2494 (2006).

    CAS  Article  Google Scholar 

  41. 41

    Shen, F., Hu, Z., Goswami, J. & Gaffen, S.L. Identification of common transcriptional regulatory elements in interleukin-17 target genes. J. Biol. Chem. 281, 24138–24148 (2006).

    CAS  Article  Google Scholar 

  42. 42

    Sato, S. et al. Essential function for the kinase TAK1 in innate and adaptive immune responses. Nat. Immunol. 6, 1087–1095 (2005).

    CAS  Article  Google Scholar 

  43. 43

    Shim, J.H. et al. TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev. 19, 2668–2681 (2005).

    CAS  Article  Google Scholar 

  44. 44

    Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).

    CAS  Article  Google Scholar 

  45. 45

    Weaver, A. et al. An elevated matrix metalloproteinase (MMP) in an animal model of multiple sclerosis is protective by affecting Th1/Th2 polarization. FASEB J. 19, 1668–1670 (2005).

    CAS  Article  Google Scholar 

  46. 46

    Becher, B., Bechmann, I. & Greter, M. Antigen presentation in autoimmunity and CNS inflammation: how T lymphocytes recognize the brain. J. Mol. Med. 84, 532–543 (2006).

    CAS  Article  Google Scholar 

  47. 47

    Gold, R., Linington, C. & Lassmann, H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129, 1953–1971 (2006).

    Article  Google Scholar 

  48. 48

    Koenders, M.I. et al. Interleukin-17 receptor deficiency results in impaired synovial expression of interleukin-1 and matrix metalloproteinases 3, 9, and 13 and prevents cartilage destruction during chronic reactivated streptococcal cell wall-induced arthritis. Arthritis Rheum. 52, 3239–3247 (2005).

    CAS  Article  Google Scholar 

  49. 49

    Liang, L., Porter, E.M. & Sha, W.C. Constitutive expression of the B7h ligand for inducible costimulator on naive B cells is extinguished after activation by distinct B cell receptor and interleukin 4 receptor-mediated pathways and can be rescued by CD40 signaling. J. Exp. Med. 196, 97–108 (2002).

    CAS  Article  Google Scholar 

  50. 50

    Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).

    CAS  Article  Google Scholar 

  51. 51

    Hjelmstrom, P., Juedes, A.E., Fjell, J. & Ruddle, N.H. B-cell-deficient mice develop experimental allergic encephalomyelitis with demyelination after myelin oligodendrocyte glycoprotein sensitization. J. Immunol. 161, 4480–4483 (1998).

    CAS  PubMed  Google Scholar 

  52. 52

    Li, Q., Estepa, G., Memet, S., Israel, A. & Verma, I.M. Complete lack of NF-κB activity in IKK1 and IKK2 double-deficient mice: additional defect in neurulation. Genes Dev. 14, 1729–1733 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Lomaga, M.A. et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 13, 1015–1024 (1999).

    CAS  Article  Google Scholar 

  54. 54

    Han, Y., Wang, J., Zhou, Z. & Ransohoff, R.M. TGFβ1 selectively up-regulates CCR1 expression in primary murine astrocytes. Glia 30, 1–10 (2000).

    CAS  Article  Google Scholar 

  55. 55

    Kordula, T. et al. Oncostatin M and the interleukin-6 and soluble interleukin-6 receptor complex regulate α1-antichymotrypsin expression in human cortical astrocytes. J. Biol. Chem. 273, 4112–4118 (1998).

    CAS  Article  Google Scholar 

Download references

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.).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Xiaoxia Li.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

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

Supplementary Table 1

Primers and oligonucleotides. (PDF 54 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

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