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Interleukin-29 induces epithelial production of CXCR3A ligands and T-cell infiltration

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Abstract

Psoriasis is considered as a model for chronic immune-mediated disorders. Th17-cells are pivotal players in those diseases. Recently, we demonstrated that Th17-cells produce interleukin (IL)-29 and that IL-29 is highly present in psoriatic lesions. Whether IL-29, with its action on epithelial cells and melanocytes, contributes to psoriasis pathogenesis, was unknown so far. Analysis of IL-29-treated human keratinocytes revealed induction of the chemokines CXCL10, CXCL11, and, to a much lesser extent, CXCL9. Unlike these CXCR3A ligands, known to attract Th1-, CD8+, NK-, and Th1/Th17 transient cells, no influence was found on chemokines attracting other immune cell populations or on molecules modulating the CXCR3A/CXCR3A ligand interaction. CXCR3A ligand expression was also induced by IL-29 in melanocytes and in epidermis models and explanted skin. Regarding other psoriasis-relevant cytokines, interferon-γ and, less potently, tumor necrosis factor-α and IL-1β shared and strengthened IL-29’s capacity. Murine IL-29 counterpart injected into mouse skin provoked local CXCL10 and CXCL11 expression, T-cell infiltration, and, in consequence, skin swelling. The elevated IL-29 expression in psoriatic lesions was associated with upregulation of CXCR3A ligands compared to non-lesional skin of these patients and to the skin of healthy donors and atopic dermatitis patients, which lack IL-29 production. Importantly, neutralization of IL-29 reduced CXCR3A ligand levels in explant cultures of psoriatic lesions. Finally, elevated blood CXCL11 levels were found in psoriasis that might be useful for monitoring lesional activity of the IL-29 axis. In summary, the Th17-cytokine IL-29 induces specific chemokines and, in consequence, provokes skin infiltration of potentially pathogenic T-cells.

Key messages

  • IL-29 selectively induces CXCR3A-binding chemokines (CXCL9, CXCL10, CXCL11) in skin cells.

  • Murine IL-29 counterpart induces skin T-cell infiltration and inflammation in mice.

  • CXCR3A ligands are IL-29-dependently increased in lesional skin of psoriasis patients.

  • CXCR3A ligand levels in psoriatic skin correlate with epidermal T-cell numbers.

  • Increased blood CXCL11 levels in psoriasis may be a biomarker for local IL-29 action.

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Acknowledgments

The authors would like to acknowledge Annette Buss and Brigitte Ketel for excellent technical assistance. This study was supported by research grant WO 1567/1-1/2 (to Kerstin Wolk) and SA1868/2 (to Robert Sabat) from the German Research Foundation (Deutsche Forschungsgemeinschaft, http://www.dfg.de/) and by a research grant 01ZX1312A from the Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, http://www.bmbf.de/) (to Kerstin Wolk and Robert Sabat).

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Authors and Affiliations

  1. Psoriasis Research and Treatment Center, University Hospital Charité, Berlin, Germany

    Ellen Witte, Georgios Kokolakis, Katrin Witte, Katarzyna Warszawska, Demetrios Christou, Stefan Kirsch, Robert Sabat & Kerstin Wolk

  2. Berlin-Brandenburg Center for Regenerative Therapies, University Hospital Charité, Berlin, Germany

    Katrin Witte, Hans-Dieter Volk & Kerstin Wolk

  3. Department of Dermatology and Allergy, University Hospital Charité, Berlin, Germany

    Markus Friedrich & Wolfram Sterry

  4. Institute of Medical Immunology, University Hospital Charité, Berlin, Germany

    Hans-Dieter Volk

  5. Research Center Immunosciences, University Hospital Charité, Berlin, Germany

    Robert Sabat & Kerstin Wolk

  6. Interdisciplinary Group Molecular Immunopathology, University Hospital Charité, Berlin, Germany

    Robert Sabat

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  1. Ellen Witte
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  2. Georgios Kokolakis
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  3. Katrin Witte
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Witte, E., Kokolakis, G., Witte, K. et al. Interleukin-29 induces epithelial production of CXCR3A ligands and T-cell infiltration. J Mol Med 94, 391–400 (2016). https://doi.org/10.1007/s00109-015-1367-y

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