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Regulation of IL-9 expression by IL-25 signaling

Nature Immunology volume 11, pages 250–256 (2010)Cite this article

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Abstract

The physiological regulation of the expression of interleukin (IL)-9, a cytokine traditionally regarded as being TH2 associated, remains unclear. Here, we show that IL-9-expressing T cells generated in vitro in the presence of transforming growth factor-β and IL-4 express high levels of mRNA for IL-17 receptor B (IL-17RB), the receptor for IL-25. Treatment of these cells with IL-25 enhances IL-9 expression in vitro. Moreover, transgenic and retroviral overexpression of IL-17RB in T cells results in IL-25-induced IL-9 production that is IL-4 independent. In vivo, the IL-25–IL-17RB pathway regulates IL-9 expression in allergic airway inflammation. Thus, IL-25 is a newly identified regulator of IL-9 expression.

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Figure 1: IL-17RB expressed by TH9 cells enhances IL-9 production.
Figure 2: IL-17RA expression in T cells is essential for IL-25 function.
Figure 3: Enhanced IL-17RB signaling induces IL-9 expression.
Figure 4: IL-17RA and IL-17RB are essential for IL-25-mediated IL-9 expression.
Figure 5: IL-9 production induced by enhanced IL-17RB signaling requires TGF-β but not IL-4.
Figure 6: IL-25-regulated IL-9 expression in CD4–IL-17RB transgenic mice exacerbates allergic lung diseases.
Figure 7: IL-25-deficiency leads to reduced IL-9 expression and airway inflammation in a mouse model of chronic allergic lung disease.

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References

  1. Van Snick, J. et al. Cloning and characterization of a cDNA for a new mouse T cell growth factor (P40). J. Exp. Med. 169, 363–368 (1989).

    Article  CAS  Google Scholar 

  2. Gessner, A., Blum, H. & Rollinghoff, M. Differential regulation of IL-9-expression after infection with Leishmania major in susceptible and resistant mice. Immunobiology 189, 419–435 (1993).

    Article  CAS  Google Scholar 

  3. Else, K.J., Hultner, L. & Grencis, R.K. Cellular immune responses to the murine nematode parasite Trichuris muris. II. Differential induction of TH-cell subsets in resistant versus susceptible mice. Immunology 75, 232–237 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Temann, U.A., Geba, G.P., Rankin, J.A. & Flavell, R.A. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J. Exp. Med. 188, 1307–1320 (1998).

    Article  CAS  Google Scholar 

  5. McLane, M.P. et al. Interleukin-9 promotes allergen-induced eosinophilic inflammation and airway hyperresponsiveness in transgenic mice. Am. J. Respir. Cell Mol. Biol. 19, 713–720 (1998).

    Article  CAS  Google Scholar 

  6. Schmitt, E. et al. IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma. J. Immunol. 153, 3989–3996 (1994).

    CAS  Google Scholar 

  7. Dardalhon, V. et al. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3− effector T cells. Nat. Immunol. 9, 1347–1355 (2008).

    Article  CAS  Google Scholar 

  8. Veldhoen, M. et al. Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat. Immunol. 9, 1341–1346 (2008).

    Article  CAS  Google Scholar 

  9. Monteyne, P. et al. IL-4-independent regulation of in vivo IL-9 expression. J. Immunol. 159, 2616–2623 (1997).

    CAS  Google Scholar 

  10. Lee, J. et al. IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1. J. Biol. Chem. 276, 1660–1664 (2001).

    Article  CAS  Google Scholar 

  11. Fort, M.M. et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15, 985–995 (2001).

    Article  CAS  Google Scholar 

  12. Angkasekwinai, P. et al. Interleukin 25 promotes the initiation of proallergic type 2 responses. J. Exp. Med. 204, 1509–1517 (2007).

    Article  CAS  Google Scholar 

  13. Wang, Y.H. et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC activated Th2 memory cells. J. Exp. Med. 204, 1837–1847 (2007).

    Article  CAS  Google Scholar 

  14. Terashima, A. et al. A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity. J. Exp. Med. 205, 2727–2733 (2008).

    Article  CAS  Google Scholar 

  15. Rickel, E.A. et al. Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities. J. Immunol. 181, 4299–4310 (2008).

    Article  CAS  Google Scholar 

  16. Sawada, S., Scarborough, J.D., Killeen, N. & Littman, D.R. A lineage-specific transcriptional silencer regulates CD4 gene expression during T lymphocyte development. Cell 77, 917–929 (1994).

    Article  CAS  Google Scholar 

  17. Chang, S.H., Park, H. & Dong, C. Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. J. Biol. Chem. 281, 35603–35607 (2006).

    Article  CAS  Google Scholar 

  18. Swaidani, S. et al. The critical role of epithelial-derived Act1 in IL-17- and IL-25-mediated pulmonary inflammation. J. Immunol. 182, 1631–1640 (2009).

    Article  CAS  Google Scholar 

  19. Claudio, E. et al. The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation. J. Immunol. 182, 1617–1630 (2009).

    Article  CAS  Google Scholar 

  20. Kung, T.T. et al. Effect of anti-mIL-9 antibody on the development of pulmonary inflammation and airway hyperresponsiveness in allergic mice. Am. J. Respir. Cell Mol. Biol. 25, 600–605 (2001).

    Article  CAS  Google Scholar 

  21. Salek-Ardakani, S. et al. OX40 (CD134) controls memory T helper 2 cells that drive lung inflammation. J. Exp. Med. 198, 315–324 (2003).

    Article  CAS  Google Scholar 

  22. Schnyder-Candrian, S. et al. Interleukin-17 is a negative regulator of established allergic asthma. J. Exp. Med. 203, 2715–2725 (2006).

    Article  CAS  Google Scholar 

  23. Houssiau, F.A., Renauld, J.C., Fibbe, W.E. & Van Snick, J. IL-2 dependence of IL-9 expression in human T lymphocytes. J. Immunol. 148, 3147–3151 (1992).

    CAS  PubMed  Google Scholar 

  24. Ballantyne, S.J. et al. Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma. J. Allergy Clin. Immunol. 120, 1324–1331 (2007).

    Article  CAS  Google Scholar 

  25. Tamachi, T. et al. IL-25 enhances allergic airway inflammation by amplifying a TH2 cell-dependent pathway in mice. J. Allergy Clin. Immunol. 118, 606–614 (2006).

    Article  CAS  Google Scholar 

  26. Ying, S., Meng, Q., Kay, A.B. & Robinson, D.S. Elevated expression of interleukin-9 mRNA in the bronchial mucosa of atopic asthmatics and allergen-induced cutaneous late-phase reaction: relationships to eosinophils, mast cells and T lymphocytes. Clin. Exp. Allergy 32, 866–871 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Rivera, S.J. Kuschert and J. Parker-Thornburg for their help in generation of knockout and transgenic animals, D. Littman (New York University School of Medicine) for the CD4 mini-gene plasmid, K. Murphy for GFP-RV vector, Amgen for IL-17-receptor deficient mice, J. van Snick for an anti–IL-9 staining antibody, B. Stockinger and M. Veldhoen for suggestions and the Dong lab members for their help and discussion. The work is supported by research grants from NIH (to C.D.). P.A. receives a fellowship from Royal Thai government and C.D. is a Trust Fellow of the MD Anderson Cancer Center and a Leukemia and Lymphoma Society Scholar.

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Authors and Affiliations

  1. Department of Immunology, University of Texas and MD Anderson Cancer Center, Houston, Texas, USA

    Pornpimon Angkasekwinai, Seon Hee Chang, Manoj Thapa & Chen Dong

  2. Department of Medical Technology, Faculty of Allied Health Sciences, Thammasat University, Pathum-thani, Thailand

    Pornpimon Angkasekwinai

  3. Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan

    Hiroshi Watarai

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  1. Pornpimon Angkasekwinai
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Contributions

P.A. and C.D. designed the research and analyzed and interpreted the results, P.A., S.H.C. and M.T. did the experiments, H.W. generated and labeled anti-IL-17RB antibody for staining and P.A. and C.D. prepared the manuscript.

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Correspondence to Chen Dong.

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Angkasekwinai, P., Chang, S., Thapa, M. et al. Regulation of IL-9 expression by IL-25 signaling. Nat Immunol 11, 250–256 (2010). https://doi.org/10.1038/ni.1846

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