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IL-19 Is a Component of the Pathogenetic IL-23/IL-17 Cascade in Psoriasis  Ellen Witte, Georgios Kokolakis, Katrin Witte, Sandra Philipp, Wolf-Dietrich.

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Presentation on theme: "IL-19 Is a Component of the Pathogenetic IL-23/IL-17 Cascade in Psoriasis  Ellen Witte, Georgios Kokolakis, Katrin Witte, Sandra Philipp, Wolf-Dietrich."— Presentation transcript:

1 IL-19 Is a Component of the Pathogenetic IL-23/IL-17 Cascade in Psoriasis 
Ellen Witte, Georgios Kokolakis, Katrin Witte, Sandra Philipp, Wolf-Dietrich Doecke, Nina Babel, Bianca M. Wittig, Katarzyna Warszawska, Agata Kurek, Magdalena Erdmann-Keding, Stefanie Kunz, Khusru Asadullah, Marshall E. Kadin, Hans-Dieter Volk, Wolfram Sterry, Kerstin Wolk, Robert Sabat  Journal of Investigative Dermatology  Volume 134, Issue 11, Pages (November 2014) DOI: /jid Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

2 Figure 1 IL-19 is highly present in the skin and blood of psoriasis patients. (a) Expression in skin biopsies from healthy individuals (n=10) and psoriasis patients (n=16, except for IL-25 (n=10)). (b) Concentration in the supernatant of skin biopsy cultures from psoriasis patients (n=5) and healthy donors (n=4) cultured for 20 hours. (c, d) Concentration in blood serum (IL-19) and plasma (IL-20, IL-22) from healthy donors (n=13), psoriasis patients (n=25); correlation with patients' psoriasis area and severity index (PASI) values. (e) Concentration in serum from healthy donors (n=26), asthma patients (n=17), patients with Crohn's disease (n=20), and transplanted patients (n=20). (f) Expression in skin biopsies from psoriasis patients before/after anti-psoriatic therapies (n=3). (g) PASI values and IL-19 serum concentrations of psoriasis patients before (PASI: 10.1±0.6)/during ustekinumab therapy (n=6) (PASI after 16wks: 4.4 ±1.0) and before (PASI: 14.1±1.4)/during UV-based combination therapy (n=6; for details refer to the Materials and Methods section) (PASI after 2–5wks: 5.4±0.7). (a–c, e–g) Mean data±s.e.m. HPRT, hypoxanthine-guanine phosphoribosyltransferase; M-CSF,macrophage colony-stimulating factor; mRNA, messenger RNA; OSM, oncostatin M; TNF-α, tumor necrosis factor-α. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

3 Figure 2 T helper type 17-cytokines drive keratinocyte IL-19 production. IL-19 expression and concentration in the supernatant of EpiDerm cultures stimulated with the indicated cytokines for 72 hours. n=3 (a,c,d,e) or n=6 (b). Mean data±s.e.m. contr., control; HPRT, hypoxanthine-guanine phosphoribosyltransferase; mRNA, messenger RNA. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

4 Figure 3 Keratinocytes are a major target of IL-19. Receptor subunit expression in isolated keratinocytes and dermal fibroblasts, microvascular endothelial cells, and melanocytes (n=2; mean ±range). HPRT, hypoxanthine-guanine phosphoribosyltransferase; mRNA, messenger RNA. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

5 Figure 4 IL-19 has no major impact on keratinocyte differentiation, proliferation, or migration. (a, b) Expression, histological appearance, and thickness of EpiDerm stimulated with the indicated cytokines for 72 hours. n=5 (a), n=7 (b, top), n=3 (IL-19), or n=6 (IL-22) (b, bottom); bar=100 μm. (c) Cell counts of keratinocytes stimulated with the indicated cytokines for 5d (n=4). Mean data±s.e.m. (a–c). (d) Confluent keratinocyte monolayers subjected to scratch wounding and subsequently stimulated with the indicated cytokines for 24 hours. Closure of wounded area monitored before (0 hours) and after (24 hours) stimulation (n=1 out of 2); bar=500 μm. CALML5, calmodulin-like 5; contr., control; DSC1, desmocollin-1; KLK7, kallikrein-7; mRNA, messenger RNA. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

6 Figure 5 IL-19 upregulates expression of selected mediators of anti-bacterial defense and inflammation in keratinocytes. (a, b) Expression in EpiDerm stimulated with the indicated cytokines for 72 hours. n=5 (a) or n=6 (b). Mean ±s.e.m. BD, β-defensin; CXCL, chemokine C-X-C motif ligand; HPRT, hypoxanthine-guanine phosphoribosyltransferase; LCN2, lipocalin-2; MMP1, matrix metalloproteinase 1. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

7 Figure 6 IL-19 provokes a strengthened IL-17A-induced keratinocyte response. (a, b) Expression and immunohistological staining of EpiDerm stimulated with the indicated cytokines for 72 hours. n=6 or (for IL-19, IL-1β, CXCL1, and chemokine C-X-C motif ligand 8 (CXCL8)) n=5 (a); and n=1 out of 4 (b); bar=100 μm. Significant differences from the IL-19/IL-17 group are indicated. (c) Concentration in the supernatant of keratinocyte cultures stimulated with the indicated cytokines for 48 hours (n=3). (d) Concentrations of tumor necrosis factor-α (TNF-α) and IL-1β in ear homogenate and ear swelling of DNFB-sensitized and DNFB-challenged or not challenged mice (n=6 per group) treated 1 hour before challenge with anti-IL-20R1 antibody (αIL-20R1), control Ab (IgG), or phosphate-buffered saline (PBS). (e) Concentrations of TNF-α and p40 in blood plasma in intraperitoneally lipopolysaccharide (LPS)-injected mice (n=5 per group) treated 16 hours before LPS application with anti-IL-20R1 Ab, control Ab, or PBS. Mean ±s.e.m. BD, β-defensin; contr., control; CCL20, chemokine C-C motif ligand 20; CXCL1, chemokine C-X-C motif ligand 1; GM-CSF, granulocyte-macrophage colony-stimulating factor; LCN2, lipocalin-2; RegIIIα, regenerating islet-derived protein 3 alpha; mRNA, messenger RNA. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

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