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Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice

Nature Immunology volume 5, pages 752–760 (2004)Cite this article

An Erratum to this article was published on 01 January 2005

Abstract

T cell–derived cytokines are important in the development of an effective immune response, but when dysregulated they can promote disease. Here we identify a four-helix bundle cytokine we have called interleukin 31 (IL-31), which is preferentially produced by T helper type 2 cells. IL-31 signals through a receptor composed of IL-31 receptor A and oncostatin M receptor. Expression of IL-31 receptor A and oncostatin M receptor mRNA was induced in activated monocytes, whereas epithelial cells expressed both mRNAs constitutively. Transgenic mice overexpressing IL-31 developed severe pruritis, alopecia and skin lesions. Furthermore, IL-31 receptor expression was increased in diseased tissues derived from an animal model of airway hypersensitivity. These data indicate that IL-31 may be involved in promoting the dermatitis and epithelial responses that characterize allergic and non-allergic diseases.

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Figure 1: IL-31 signals through IL-31RA and OSMR.
Figure 2: Expression analysis of IL-31 by real-time PCR.
Figure 3: Expression analysis of IL-31RA and OSMR mRNA in human and mouse samples by real-time PCR.
Figure 4: IL-31-transgenic lesional skin is characterized by many hallmarks of atopic dermatitis.
Figure 5: IL-31-transgenic mice have enlarged peripheral lymph nodes containing an inverted ratio of T lymphocytes to B lymphocytes and an increased number of activated CD4+ and CD8+ T cells.
Figure 6: Intradermal injection of IL-31 causes cell infiltration and acanthosis.
Figure 7: IL-31RA-deficient mice do not develop pruritis or alopecia when given mouse IL-31 by osmotic pump.
Figure 8: IL-31RA mRNA is upregulated in lung and bronchoalveolar lavage cells after allergen sensitization.

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Acknowledgements

We thank K. Kim, K. Bontadelli and D. Cutler for help with the generation and analysis of the IL-31-transgenic mice; K. Bannink for the IL-31 in vivo treatment studies; T. Whitmore for insights regarding the gene array analysis and genetic linkage analysis; and M. Bernard for assistance in preparing the manuscript.

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Author notes

  1. Stacey R Dillon and Cindy Sprecher: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, ZymoGenetics, 1201 Eastlake Avenue East, Seattle, 98102, Washington, USA

    Stacey R Dillon, Janine Bilsborough, Mark Maurer, Brandon Harder, Janet Johnston, Susan Bort, Sherri Mudri & Jane A Gross

  2. Department of Cytokine Biology, ZymoGenetics, 1201 Eastlake Avenue East, Seattle, 98102, Washington, USA

    Cindy Sprecher, Angela Hammond, Joseph L Kuijper, Maria Dasovich, Steven D Levin, Janet Kramer, Rolf Kuestner, Don Foster & Julia Parrish-Novak

  3. Department of Pre-clinical Development, ZymoGenetics, 1201 Eastlake Avenue East, Seattle, 98102, Washington, USA

    Maryland Rosenfeld-Franklin & Kim Waggie

  4. Department of Scientific Computing, ZymoGenetics, 1201 Eastlake Avenue East, Seattle, 98102, Washington, USA

    Scott R Presnell & Francis J Grant

  5. Department of Genetics, ZymoGenetics, 1201 Eastlake Avenue East, Seattle, 98102, Washington, USA

    Harald S Haugen, Luann Lockwood, Cosette LeCiel & Zhi Chen

  6. Department of Protein Biochemistry, ZymoGenetics, 1201 Eastlake Avenue East, Seattle, 98102, Washington, USA

    Tom Bukowski, Pamela Shea & Dennis L Dong

  7. Department of In Vitro Biology, ZymoGenetics, 1201 Eastlake Avenue East, Seattle, 98102, Washington, USA

    Heather Day & Stavros Topouzis

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Correspondence to Jane A Gross.

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The authors of this manuscript are employed or previously employed by ZymoGenetics Inc. and may or may not benefit financially from the publication of this paper.

Supplementary information

Supplementary Table 1

STAT activation by IL-31 in human cells (PDF 4 kb)

Supplementary Table 2

Induction of chemokine genes in IL-31-treated keratinocytes (PDF 5 kb)

Supplementary Table 3

Extent and timing of skin phenotype in IL-31 Tg mice (PDF 5 kb)

Supplementary Table 4

Lymphoid and myeloid cell development is normal in IL-31RA-deficient mice (PDF 6 kb)

Supplementary Note (XLS 31 kb)

Supplementary Methods (PDF 5 kb)

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Dillon, S., Sprecher, C., Hammond, A. et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol 5, 752–760 (2004). https://doi.org/10.1038/ni1084

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