title: Interleukin-29 induces epithelial production of CXCR3A ligands and T-cell infiltration.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Psoriasis Research and Treatment Center, University Hospital Charité, Berlin, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Witte
authors.affiliation: Psoriasis Research and Treatment Center, University Hospital Charité, Berlin, Germany.
authors.forename: Georgios
authors.initials: G
authors.lastname: Kokolakis
authors.affiliation: Psoriasis Research and Treatment Center, University Hospital Charité, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies, University Hospital Charité, Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Witte
authors.affiliation: Psoriasis Research and Treatment Center, University Hospital Charité, Berlin, Germany.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Warszawska
authors.affiliation: Department of Dermatology and Allergy, University Hospital Charité, Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Friedrich
authors.affiliation: Psoriasis Research and Treatment Center, University Hospital Charité, Berlin, Germany.
authors.forename: Demetrios
authors.initials: D
authors.lastname: Christou
authors.affiliation: Psoriasis Research and Treatment Center, University Hospital Charité, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kirsch
authors.affiliation: Department of Dermatology and Allergy, University Hospital Charité, Berlin, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Sterry
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, University Hospital Charité, Berlin, Germany.|Institute of Medical Immunology, University Hospital Charité, Berlin, Germany.
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.affiliation: Psoriasis Research and Treatment Center, University Hospital Charité, Berlin, Germany.|Research Center Immunosciences, University Hospital Charité, Berlin, Germany.|Interdisciplinary Group Molecular Immunopathology, University Hospital Charité, Berlin, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Sabat
authors.affiliation: Psoriasis Research and Treatment Center, University Hospital Charité, Berlin, Germany. kerstin.wolk@charite.de.|Berlin-Brandenburg Center for Regenerative Therapies, University Hospital Charité, Berlin, Germany. kerstin.wolk@charite.de.|Research Center Immunosciences, University Hospital Charité, Berlin, Germany. kerstin.wolk@charite.de.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wolk
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis; D004848:Epithelium / Q000276:immunology* / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008875:Middle Aged; D011565:Psoriasis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D054367:Receptors, CXCR3 / Q000096:biosynthesis*; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D055815:Young Adult; D000095022:Interferon Lambda
chemical_list: D018925:Chemokines; D007372:Interferons; D007378:Interleukins; D008024:Ligands; D054367:Receptors, CXCR3; C000624353:interferon-lambda, human; D000095022:Interferon Lambda
keywords: Biomarker; Chemokine; Cytokine; Infiltration; Interferon-lambda; Skin disease