Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin Giulia Fornasa, PhD, Katerina Tsilingiri,

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Presentation transcript:

Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin Giulia Fornasa, PhD, Katerina Tsilingiri, PhD, Flavio Caprioli, MD, PhD, Fiorenzo Botti, MD, Marina Mapelli, PhD, Stephan Meller, MD, Andreas Kislat, MSc, Bernhard Homey, MD, Antonio Di Sabatino, MD, Angelica Sonzogni, MD, Giuseppe Viale, MD, PhD, Giuseppe Diaferia, PhD, Alessandro Gori, PhD, Renato Longhi, PhD, Giuseppe Penna, MSc, Maria Rescigno, PhD Journal of Allergy and Clinical Immunology Volume 136, Issue 2, Pages 413-422 (August 2015) DOI: 10.1016/j.jaci.2015.04.011 Copyright © 2015 The Authors Terms and Conditions

Fig 1 shTSLP is the predominant isoform expressed on human intestinal and skin tissue. A, Schematic representation of the human TSLP locus from the UCSC Genome Browser (hg19). B and C, Quantitative real-time PCR analysis of shTSLP and lTSLP mRNA in intestinal total tissue, isolated intestinal epithelial cells (IECs), and lamina propria (LP) cells (Fig 1, B) and skin samples (Fig 1, C) from healthy subjects. ***P < .001. Journal of Allergy and Clinical Immunology 2015 136, 413-422DOI: (10.1016/j.jaci.2015.04.011) Copyright © 2015 The Authors Terms and Conditions

Fig 2 shTSLP has anti-inflammatory properties. A, IFN-γ production in a bidirectional mixed lymphocyte reaction in the presence of shTSLP and lTSLP. Results of 3 independent experiments are shown. B, Inflammatory cytokine secretion of moDCs conditioned with shTSLP and then infected with Salmonella typhimurium. Results of 4 independent experiments are shown. Data are expressed as a “fold change” considering untreated PBMCs or cells treated only with Salmonella typhimurium as a control (value = 1). Significant differences were determined by means of 1-way ANOVA with the Dunnett test. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2015 136, 413-422DOI: (10.1016/j.jaci.2015.04.011) Copyright © 2015 The Authors Terms and Conditions

Fig 3 shTSLP increases p38α phosphorylation in moDCs. A, Human phosphokinase array assay of moDCs left untreated or conditioned for 5 and 20 minutes with 100 ng/mL short TSLP. B, Quantification of p38α phosphorylation in untreated and shTSLP-stimulated moDCs by means of Western blotting: representative membranes from 2 donors (upper panel) and quantification analysis of 4 independent donors (lower panel). Values are normalized against total p38α protein levels and compared with untreated cells. Journal of Allergy and Clinical Immunology 2015 136, 413-422DOI: (10.1016/j.jaci.2015.04.011) Copyright © 2015 The Authors Terms and Conditions

Fig 4 Effects of shTSLP on mDCs in vitro. A, Fluorescence-activated cell sorting analysis of phospho-STAT5 on mDCs left untreated or incubated with shTSLP, lTSLP, or both. B, ELISA of CCL17 and CCL22 levels in supernatants of mDCs treated as in Fig 4, A. Results of 2 independent experiments are shown. The same cells were washed and cultured with naive CD4+ T cells. C and D, Intracellular staining for TNF (Fig 4, C) and detection of IFN-γ in supernatants (Fig 4, D) were performed after 6 days of coculture. Fig 4, C, Results of 4 independent experiments are shown. Fig 4, D, Data show a representative of 3 independent experiments. Significant differences were determined by using 1-way ANOVA with the Tukey test. In Fig 4, A and C, a significant increase over untreated cells is indicated by asterisks. *P < .05 and ***P < .001. Journal of Allergy and Clinical Immunology 2015 136, 413-422DOI: (10.1016/j.jaci.2015.04.011) Copyright © 2015 The Authors Terms and Conditions

Fig 5 shTSLP has anti-inflammatory effects in vivo. A, Cytokine levels in the sera of mice treated intraperitoneally with shTSLP 18 hours and 2 hours before inducing LPS shock. Blood was collected 6 hours later. Results of 2 independent experiments are shown. Significant differences were determined by using 1-way ANOVA with the Dunnett test. B, Body weight changes in mice with DSS-induced colitis treated with shTSLP or vehicle intraperitoneally. The graph shows the percentage of body weight relative to initial body weight. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2015 136, 413-422DOI: (10.1016/j.jaci.2015.04.011) Copyright © 2015 The Authors Terms and Conditions

Fig 6 TSLP isoforms are differentially expressed in the intestines of patients with UC and those with CD compared with healthy subjects and differentially modulated in epithelial cells. A and C, Quantitative PCR analysis of shTSLP and lTSLP in epithelial and LP cells from tissues of healthy subjects (H; n = 26) patients with UC (n = 13; Fig 6, A) or biopsy specimens of patients with untreated CD (UCD; n = 13), patients with treated CD (TCD, n = 15), patients with CD, and healthy subjects (n = 13; Fig 6, C). B, Representative immunofluorescent stainings of lTSLP (upper panels, red), both TSLP isoforms (bottom panels, red), and CD14+ cells (green) in sections of colon. D, Quantification of TSLP isoforms protein expression in untreated or infected Caco-2 cells. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2015 136, 413-422DOI: (10.1016/j.jaci.2015.04.011) Copyright © 2015 The Authors Terms and Conditions

Fig 7 shTSLP and lTSLP are differentially expressed in skin tissue of patients with AD. A, Quantitative PCR analysis of shTSLP and lTSLP in skin biopsy specimens from nonlesional (NL) and lesional (L) skin of patients with AD (n = 24). B, Representative immunfluorescencent staining of lTSLP (upper panels, red) and both TSLP isoforms (bottom panels, red) in tissue sections of nonlesional and lesional skin. C and D, ChIP–quantitative PCR analysis of H3K27Ac-enriched regions in the promoters of the TSLP isoforms (Fig 7, C) and mRNA levels of TSLP isoforms (Fig 7, D) in untreated HEKa or those stimulated with vitamin D3 (10 μmol/L) and poly I:C (5 μg/mL). *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2015 136, 413-422DOI: (10.1016/j.jaci.2015.04.011) Copyright © 2015 The Authors Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2015 136, 413-422DOI: (10.1016/j.jaci.2015.04.011) Copyright © 2015 The Authors Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2015 136, 413-422DOI: (10.1016/j.jaci.2015.04.011) Copyright © 2015 The Authors Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2015 136, 413-422DOI: (10.1016/j.jaci.2015.04.011) Copyright © 2015 The Authors Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2015 136, 413-422DOI: (10.1016/j.jaci.2015.04.011) Copyright © 2015 The Authors Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2015 136, 413-422DOI: (10.1016/j.jaci.2015.04.011) Copyright © 2015 The Authors Terms and Conditions

Fig E6 Journal of Allergy and Clinical Immunology 2015 136, 413-422DOI: (10.1016/j.jaci.2015.04.011) Copyright © 2015 The Authors Terms and Conditions

Fig E7 Journal of Allergy and Clinical Immunology 2015 136, 413-422DOI: (10.1016/j.jaci.2015.04.011) Copyright © 2015 The Authors Terms and Conditions

Fig E8 Journal of Allergy and Clinical Immunology 2015 136, 413-422DOI: (10.1016/j.jaci.2015.04.011) Copyright © 2015 The Authors Terms and Conditions