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Treatment Proinflammatory Mediators Upon Dendritic Cells Activated by IFN-γ/STAT1 Express IL-31 Receptor and Release Proinflammatory Mediators upon IL-31 Treatment This information is current as of September 25, 2021. Jutta Horejs-Hoeck, Harald Schwarz, Sebastian Lamprecht, Elisabeth Maier, Stefan Hainzl, Maria Schmittner, Gernot Posselt, Angelika Stoecklinger, Thomas Hawranek and Albert Duschl J Immunol 2012; 188:5319-5326; Prepublished online 25 Downloaded from April 2012; doi: 10.4049/jimmunol.1101044 http://www.jimmunol.org/content/188/11/5319 http://www.jimmunol.org/ References This article cites 67 articles, 31 of which you can access for free at: http://www.jimmunol.org/content/188/11/5319.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 25, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Dendritic Cells Activated by IFN-g/STAT1 Express IL-31 Receptor and Release Proinflammatory Mediators upon IL-31 Treatment Jutta Horejs-Hoeck,* Harald Schwarz,* Sebastian Lamprecht,* Elisabeth Maier,* Stefan Hainzl,*,† Maria Schmittner,* Gernot Posselt,* Angelika Stoecklinger,*,‡ Thomas Hawranek,x and Albert Duschl* IL-31 is a T cell-derived cytokine that signals via a heterodimeric receptor composed of IL-31Ra and oncostatin M receptor b. Although several studies have aimed to investigate IL-31–mediated effects, the biological functions of this cytokine are currently not well understood. IL-31 expression correlates with the expression of IL-4 and IL-13 and is associated with atopic dermatitis in humans, indicating that IL-31 is involved in Th2-mediated skin inflammation. Because dendritic cells are the main activators of Downloaded from Th cell responses, we posed the question of whether dendritic cells express the IL-31R complex and govern immune responses triggered by IL-31. In the current study, we report that primary human CD1c+ as well as monocyte-derived dendritic cells significantly upregulate the IL-31Ra receptor chain upon stimulation with IFN-g. EMSAs, chromatin immunoprecipitation assays, and small interfering RNA-based silencing assays revealed that STAT1 is the main transcription factor involved in IFN-g–dependent IL-31Ra expression. Subsequent IL-31 stimulation resulted in a dose-dependent release of proinflammatory mediators, including TNF-a, IL-6, CXCL8, CCL2, CCL5, and CCL22. Because these cytokines are crucially involved in skin http://www.jimmunol.org/ inflammation, we hypothesize that IL-31–specific activation of dendritic cells may be part of a positive feedback loop driving the progression of inflammatory skin diseases. The Journal of Immunology, 2012, 188: 5319–5326. nterleukin-31 is a four-helix bundle cytokine closely related to pathways downstream of the receptor demonstrated activation of the IL-6 cytokine family (1). The main sources of IL-31 are p38MAPK, ERK1/2, and JNK1/2, and phosphorylation of the T cells, in particular activated CD4+ T cells such as skin- STAT family members STAT1, STAT3, and STAT5 (1, 5, 7, 9, 10). I + infiltrating cutaneous lymphocyte Ag memory T cells (1–3) and At present, little is known about the biological consequences of T cells activated under Th2 skewing conditions (1). IL-31 signaling. Transgenic mice overexpressing IL-31 develop a by guest on September 25, 2021 A very recent study suggests that mast cells are an additional severe skin phenotype closely resembling the skin from patients source of IL-31: human mast cells secrete IL-31 and other pru- with atopic dermatitis (AD) (1, 11). Analysis of skin biopsies from ritogenic mediators upon stimulation with human b-defensins and patients with different types of inflammatory skin diseases showed cathelicidin (4). that IL-31 is overexpressed predominantly in pruritic forms of IL-31 signals via a heterodimeric receptor complex composed of skin inflammation (12). Moreover, leukocytes from patients with IL-31Ra (IL-31RA), previously termed gp130-like monocyte re- AD or allergic contact dermatitis (ACD) show significantly en- ceptor (5) or gp130-like receptor (6, 7), and oncostatin M receptor hanced IL-31 expression that is associated with elevated expres- b (OSMRB) (1, 8). Several in vitro studies investigating signaling sion of IL-4 and IL-13 as compared with healthy volunteers (3, 12). On the basis of these findings, IL-31 has recently begun to be looked at as a possible mediator in the pathogenesis of Th2 *Department of Molecular Biology, University of Salzburg, A-5020 Salzburg, Aus- tria; †Laboratory for Immunological and Molecular Cancer Research, 3rd Medical cytokine-mediated inflammatory skin diseases like AD and ACD. Department, Paracelsus Medical University, A-5020 Salzburg, Austria; ‡Christian In contrast, other published studies support a role for IL-31– Doppler Laboratory for Allergy Diagnosis and Therapy, A-5020 Salzburg, Aus- x induced signaling in limiting the severity of Th2-mediated inflam- tria; and Department of Dermatology, Paracelsus Medical University, A-5020 Salz- burg, Austria mation in the lung and gut (13, 14). For example, IL-31RA–defi- Received for publication April 11, 2011. Accepted for publication March 30, 2012. cient mice injected with Schistosoma mansoni eggs developed This work was supported by the University of Salzburg priority program BioScience a more severe pulmonary Th2 inflammation than did wild-type and Health and Austrian Fond zur Fo¨rderung der Wissenschaftlichen Forschung (WT) animals. The results of a similar study likewise suggest Grant P22202. E.M. is a recipient of a DOC-fFORTE-fellowship of the Austrian a regulatory role for IL-31/IL-31R interactions in the intestine Academy of Sciences at the Department of Molecular Biology, University of Salz- burg. following infection with the gastrointestinal helminth Trichuris Address correspondence and reprint requests to Dr. Jutta Horejs-Hoeck, Department muris (14). Taken together, these data indicate that IL-31/IL- of Molecular Biology, University of Salzburg, Hellbrunner Strasse 34, A-5020 Salz- 31R interactions may play an important role in limiting Th2- burg, Austria. E-mail address: [email protected] mediated inflammatory responses in the lung and the intestine, Abbreviations used in this article: ACD, allergic contact dermatitis; AD, atopic whereas, in the skin, IL-31 action is positively correlated with dermatitis; ChIP, chromatin immunoprecipitation; DC, dendritic cell; GAS, g-acti- vation sequence; IL-31RA, IL-31Ra; moDC, monocyte-derived DC; OSMRB, inflammation. oncostatin M receptor b; qRT-PCR, quantitative real-time PCR; SEB, staphylococcal Dendritic cells (DCs) are highly specialized, professional APCs enterotoxin B; siRNA, small interfering RNA; TARC, thymus- and activation-regu- equipped with a plethora of intracellular and extracellular pattern lated chemokine; TSLP, thymic stromal lymphopoietin; WT, wild-type. recognition receptors. Upon activation by various stimuli, DCs Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 undergo a maturation process that endows them with distinct DC www.jimmunol.org/cgi/doi/10.4049/jimmunol.1101044 5320 DENDRITIC CELLS EXPRESS IL-31R UPON IFN-g/STAT1 SIGNALING functions, including capture and presentation of Ag, migration, (MBI Fermentas, St. Leon-Roth, Germany), according to the manu- costimulation, and the release of T cell-polarizing cytokines (15). facturer’s instructions. Quantitative real-time RT-PCR (qRT-PCR) was Because DCs are the main orchestrators of T cell responses, we carried out on a Rotorgene 3000 (Corbett Research, Mortlake, Australia) using iQ SYBR Green Supermix (Bio-Rad) and the primers listed below. sought to address a potential contribution of DCs to the complex The large ribosomal protein P0 (RPLP0) was used as a reference. The picture of IL-31–mediated effects. As none of the studies ana- specificity of the PCRs was checked by recording a melting curve for the lyzing IL-31R expression has reported on its expression on DCs, PCR products. Relative mRNA expression levels were calculated using the 2DCt IL-31–mediated effects on DCs have remained speculative to date. formula x =2 , where Ct represents the threshold cycle of a given gene and DCt signifies the difference between the Ct values of the gene in In this study, we show that IL-31RA surface expression on DCs is question and the Ct value of the reference gene RPLP0. Induction ratios enhanced in response to IFN-g. Moreover, we demonstrate that the were calculated using the formula x =22DDCt. DDCt represents the dif- transcription factor STAT1 is crucial for IFN-g–dependent IL- ference between the DCt values of induced and uninduced samples. 31RA expression. Once DCs express the cognate receptor, they Primer sequences are as follows: human IL-31RA sense, 59-GGCA- become responsive to IL-31 and secrete substantial
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