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Recapitulates Some Features of Psoriasis Α , And The Journal of Immunology Skin Inflammation Induced by the Synergistic Action of IL-17A, IL-22, Oncostatin M, IL-1a, and TNF-a Recapitulates Some Features of Psoriasis Karline Guilloteau,*,† Isabelle Paris,*,‡ Nathalie Pedretti,*,† Katia Boniface,*,1 Franck Juchaux,*,† Vincent Huguier,x Gerard Guillet,{ Franc¸ois-Xavier Bernard,*,† Jean-Claude Lecron,*,‡ and Franck Morel* Keratinocytes play a crucial role in the regulation of skin inflammation, responding to environmental and immune cells stimuli. They produce soluble factors that can act in an autocrine or paracrine manner on immune cells or directly on aggressors. A screen- ing of the activities of 36 cytokines on keratinocyte gene expression identified IL-17A, IL-22, oncostatin M, TNF-a, and IL-1a as potent cytokines in inducing cutaneous inflammation. These five proinflammatory cytokines synergistically increased production of CXCL8 and b-defensin 2 (BD2). In addition, ex vivo studies on human skin explants demonstrated upregulation of BD2, S100A7, and CXCL8 expression in response to the same combination of cytokines. In vivo intradermal injection of these five cytokines in mouse increased CXCL1, CXCL2, CXCL3, S100A9, and BD3 expression, associated with neutrophil infiltration. We confirmed and extended this synergistic effect using quantitative real-time PCR analysis and observed increased expression of nine chemokines and 12 antimicrobial peptides. Production of CXCL, CXCL5, and CXCL8 by keratinocytes stimulated in the presence of this cytokine combination was associated with increased neutrophil chemotactic activity. Similarly, high production of BD2, BD3, and S100A7 was associated with an increased antimicrobial activity. Finally, the transcriptional profile observed in this in vitro model of inflammatory keratinocytes correlated with the one of lesional psoriatic skin. Our results demonstrate the important potentiating activities of IL-17A, IL-22, oncostatin M, TNF-a, and IL-1a on keratinocytes. This is particularly in- teresting in the context of psoriasis where these cytokines are overexpressed and could synergize to play an important role in upregulation of chemokines and antimicrobial peptides production. The Journal of Immunology, 2010, 184: 5263–5270. eratinocytes play an important role in the regulation of keratinocyte (NHEK) cultures with those of human biopsies from skin inflammation, responding to environmental and inflammatory cutaneous diseases, especially psoriasis, revealed K immune cells stimuli. Over the past few years, an in- a number of common features. Indeed, IL-1a, IL-22, TNF-a, and creasing number of reports has demonstrated that keratinocytes are oncostatin M (OSM) induce a “psoriasiform” profile on NHEKs direct targets for a specific set of cytokines, leading to the regu- in vitro (1–4, 7). These in vitro studies identified cytokines able to lation of their biological properties, such as secretion of cytokines, induce specific expression patterns related to innate immune re- chemokines, and antimicrobial peptides, their differentiation and sponse, such as IL-1a, TNF-a, or IL-17A, or related to the ker- migration capacities (1–6). The comparison of the biological atinocyte differentiation program, such as IL-22 or OSM. Some of profile induced in vitro by cytokines on normal human epidermal these cytokines, or related ones, such as IL-1a, IL-22, or IL-23, can induce skin inflammation in animal models (7–10). Moderate to full redundancy within each cytokine family has also been *Laboratoire Inflammation, Tissus Epithe´liaux et Cytokines, Unite´s Propres de described for IL-1, IL-6, IL-10, IL-17, and TNF families (11–17). Recherche, Equipe d’Accueil, Poˆle Biologie Sante´ and ‡Laboratoire Prote´ines et Inflammation, Centre Hospitalier Universitaire de Poitiers, Poˆle Biologie Sante´, It appears that single cytokine stimulation generates a rather Universite´ de Poitiers; xService de Chirurgie Plastique, and {Service de Dermato- limited effect on keratinocytes, namely, a limited number and/or † logie, Centre Hospitalier Universitaire de Poitiers, Poitiers; and BIOalternatives, a limited modulated expression of targeted genes, reflecting only Genc¸ay, France partial features with psoriasis. Recent data showing that immune 1Current address: Department of Immunology, Schering-Plough Biopharma, Palo Alto, CA. cells infiltrating psoriatic skin secreted large amounts of several Received for publication July 29, 2009. Accepted for publication February 25, 2010. inflammatory cytokines, including IL-22, IL-17A, and IL-23, led to classify psoriasis as the paradigm of an inflammatory disease This work was supported by grants from a clinical research program from Poitiers University Hospital, La Ligue Contre le Cancer, Association Nationale de Recherche involving the proinflammatory Th17 subset, challenging the Th1 et de la Technologie, and from le Conseil Re´gional de la Re´gion Poitou-Charentes. K.G. theory previously admitted (4, 18–21). We previously reported was supported by Convention Industrielle de Formation par la Recherche financing. that supernatants from T cells isolated from psoriatic skin were Address correspondence and reprint requests to Dr. Franck Morel and Dr. Jean- able to induce a “psoriasis-like” phenotype in NHEKs (18, 21), Claude Lecron, Laboratoire Inflammation, Tissus Epithe´liaux et Cytokines, UPRES EA 4331, Poˆle Biologie Sante´, 40 Avenue du Recteur Pineau, Universite´ de Poitiers, which would result from synergistic effects among the cytokines 86022 Poitiers Cedex, France. E-mail addresses: [email protected] and jean- produced by these T cells. For example combination of IL-17A [email protected] and IFN-g or IL-17A and TNF-a results in a synergistic effect on The online version of this article contains supplemental material. CXCL8 production (22, 23). IL-17A and IL-22 synergize in the Abbreviations used in this paper: BD, b-defensin; NHEK, normal human epidermal ker- upregulation of b-defensin 2 (BD2) and S100A9 production (24). atinocyte; NI, noninjected; OSM, oncostatin M; QRT-PCR, quantitative real-time PCR. Our goal was to identify an optimal and relevant cytokine com- Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 bination able to synergize to generate in vitro an inflammatory www.jimmunol.org/cgi/doi/10.4049/jimmunol.0902464 5264 CYTOKINE-INDUCED KERATINOCYTE INFLAMMATION keratinocyte model recapitulating some features of lesional pso- was taken after 24 h of treatment at the site of injection and immediately riatic skin. frozen in liquid nitrogen for RNA quantification. Culture supernatants were collected for cytokine ELISA determination. Materials and Methods Macroarrays analysis Skin samples The comparison of the effects of 36 different cytokines on the expression of 154 genes of potential interest for skin physiology was performed using The use of skin samples for this study was approved by the Ethical home-made cDNA macroarrays analysis (Supplemental Table I). After Committee of the Poitiers Hospital. After informed consent, lesional skin cytokine stimulation, total RNA was extracted using TRIzol Reagent biopsies were obtained from eight different patients with moderate-to- (Invitrogen Life Technologies, Cergy Pontoise, France) and conventional severe plaque psoriasis (mean age = 47 y; skin involvement 30–90% of body 33P-cDNA target synthesis and hybridization were performed (4). Genes . surface area) that did not receive any therapy for 4 wk. Normal skin were considered regulated if expression levels differed .3-fold relative to biopsies were obtained from surgical samples of healthy breast skin. untreated control and 3-fold relative to mean background noise. Cell cultures, cytokines, and reagents Real-time PCR analysis NHEK were obtained as previously described, from surgical samples of NHEK and skin total RNAwere isolatedand reverse transcribedas previously healthy breast skin (1). NHEK were cultured to 80% of confluence and then described (1). Quantitative real-time PCR (QRT-PCR) was carried using starved for 24 h in Keratinocyte serum-free medium without addition of the LightCycler-FastStart DNA MasterPlus SYBR Green I kit on LightCycler growth factors before stimulation. Cells were stimulated with or without 480 (Roche Diagnostics, Meylan, France). The reaction components were 10 ng/ml recombinant IL-17A, OSM, TNF-a, IL-22, and IL-1a alone or in 13 DNA Master Mix, and 0.5 mM HPLC purified sense and antisense oli- combination (R&D Systems Europe, Lille, France) during 24 h for mRNA gonucleotides purchased from Eurogentec (Eurogentec France, Angers, quantification or 48–96 h for protein quantification. France), designed using Primer3 software. Samples were normalized to In vivo murine skin inflammation. Outbred OF1 mice were purchased from three independent control housekeeping genes (G3PDH, RPL13A, or ACTB Charles River Laboratories (Chatillon, France). Ear intradermally injections for human samples and G3PDH, HMBS, or b2-microglobulin for mouse samples) and reported according to the ΔΔCT method as RNA fold increase: were realized at day 0 under brief isoflurane (Forene, Abott France, Rungis, ΔΔCT ΔCT sample 2 ΔCT reference France) gas anesthesia. The 250 ng carrier-free IL-17A, OSM, TNF-a, IL-22, 2 =2 . For comparison of normal skin and pso- and IL-1a (R&D Systems Europe) or PBS or 10 mg LPS (Sigma-Aldrich, riatic skin the REST 2008 software was used (25). Saint Quentin Fallavier, France) were injected in a total volume of 20 ml. After Cytokine measurement by ELISA. Levels of BD2, BD3,
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