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Targeting Serine/Threonine Kinase 40 Chemokine Production in Keratinocytes Via and Modulates Inflammatory Cytokine and Microrna

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Targeting Serine/Threonine Kinase 40 Chemokine Production in Keratinocytes Via and Modulates Inflammatory Cytokine and Microrna MicroRNA-31 Is Overexpressed in Psoriasis and Modulates Inflammatory Cytokine and Chemokine Production in Keratinocytes via Targeting Serine/Threonine Kinase 40 This information is current as of September 26, 2021. Ning Xu, Florian Meisgen, Lynn M. Butler, Gangwen Han, Xiao-Jing Wang, Cecilia Söderberg-Nauclér, Mona Ståhle, Andor Pivarcsi and Enikö Sonkoly J Immunol published online 10 December 2012 http://www.jimmunol.org/content/early/2012/12/10/jimmun Downloaded from ol.1202695 Supplementary http://www.jimmunol.org/content/suppl/2012/12/10/jimmunol.120269 http://www.jimmunol.org/ Material 5.DC1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 26, 2021 • 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. Published December 10, 2012, doi:10.4049/jimmunol.1202695 The Journal of Immunology MicroRNA-31 Is Overexpressed in Psoriasis and Modulates Inflammatory Cytokine and Chemokine Production in Keratinocytes via Targeting Serine/Threonine Kinase 40 Ning Xu,* Florian Meisgen,* Lynn M. Butler,† Gangwen Han,‡ Xiao-Jing Wang,‡ Cecilia So¨derberg-Naucle´r,† Mona Sta˚hle,* Andor Pivarcsi,* and Eniko¨ Sonkoly* Psoriasis is characterized by a specific microRNA expression profile, distinct from that of healthy skin. MiR-31 is one of the most highly overexpressed microRNAs in psoriasis skin; however, its biological role in the disease has not been studied. In this study, we show that miR-31 is markedly overexpressed in psoriasis keratinocytes. Specific inhibition of miR-31 suppressed NF-kB–driven promoter luciferase activity and the basal and TNF-a–induced production of IL-1b, CXCL1/growth-related oncogene-a, CXCL5/ epithelial-derived neutrophil-activating peptide 78, and CXCL8/IL-8 in human primary keratinocytes. Moreover, interference with Downloaded from endogenous miR-31 decreased the ability of keratinocytes to activate endothelial cells and attract leukocytes. By microarray expression profiling, we identified genes regulated by miR-31 in keratinocytes. Among these genes, we identified serine/threonine kinase 40 (STK40), a negative regulator of NF-kB signaling, as a direct target for miR-31. Silencing of STK40 rescued the suppressive effect of miR-31 inhibition on cytokine/chemokine expression, indicating that miR-31 regulates cytokine/chemokine expression via targeting STK40 in keratinocytes. Finally, we demonstrated that TGF-b1, a cytokine highly expressed in psoriasis epidermis, upregulated miR-31 expression in keratinocytes in vitro and in vivo. Collectively, our findings suggest that overexpres- http://www.jimmunol.org/ sion of miR-31 contributes to skin inflammation in psoriasis lesions by regulating the production of inflammatory mediators and leukocyte chemotaxis to the skin. Our data indicate that inhibition of miR-31 may be a potential therapeutic option in psoriasis. The Journal of Immunology, 2013, 190: 000–000. soriasis is a common chronic inflammatory skin disease, epidermis (1). There is a close interdependence between kerati- which affects 2–3% of the population. It is a lifelong nocytes and immune cells in psoriatic skin: the cytokines and P disease with spontaneous remissions and exacerbations chemokines secreted by keratinocytes, such as IL-1b,TNF-a, that are severely detrimental to the patients’ quality of life (1). CXCL1/growth-related oncogene-a, CXCL5/epithelial-derived Psoriasis skin lesions are typically characterized by keratinocyte neutrophil-activating peptide 78, and CXCL8/IL-8 activate and by guest on September 26, 2021 hyperproliferation and aberrant differentiation, increased vascu- attract immune cells to migrate into epidermis and dermis; immune larity in the dermis, and infiltration of inflammatory cells, such as cell–derived cytokines, in turn, act on keratinocytes to increase the macrophages, neutrophils, and lymphocytes into the dermis and expression of inflammatory genes, promote keratinocyte prolifer- ation, and impair keratinocyte differentiation (reviewed in Ref. 1). microRNAs (miRNAs) are ∼ 22nt long single-stranded noncoding *Molecular Dermatology Research Group, Unit of Dermatology and Venereology, Department of Medicine, Karolinska Institute, SE-17176 Stockholm, Sweden; RNAs that mediate posttranscriptional silencing by binding with †Cell and Molecular Immunology Group, Department of Medicine, Karolinska In- ‡ partial complementarity to the 39-untranslated region (39-UTR) of stitute, SE-17176 Stockholm, Sweden; and Department of Pathology, University of ∼ Colorado Denver, Aurora, CO 80045 target mRNA (2). miRNAs are estimated to regulate 60% of all protein-coding genes in humans and have been shown to participate Received for publication September 26, 2012. Accepted for publication November 5, 2012. in the regulation of almost every cellular process investigated to date This work was supported by the Swedish Research Council (Vetenskapsra˚det), the (3). We and others have previously identified a distinct miRNA Swedish Society of Medicine (Svenska La¨karesa¨llskapet), the Swedish Psoriasis expression profile in psoriasis skin compared with healthy skin (4– Association (Psoriasisfo¨rbundet), the European Skin Research Foundation, the 8). Several of these deregulated miRNAs have been shown to act on Welander and Finsens Foundation, the Tore Nilssons Foundation, the Lars Hierta Memorial Foundation, the Sigurt and Elsa Golje Memorial Foundation, the Centre of cellular processes crucial for psoriasis. For example, miR-203 (7), Excellence for Research on Inflammation and Cardiovascular Disease, the Karolinska miR-125b (9), miR-424 (4), and miR-99a (6) regulate keratinocyte Institute, and the Stockholm County Council. N.X. was supported by the Swedish Society for Medical Research. A.P. was supported by the LEO Pharma Research proliferation and differentiation, whereas miR-21 suppresses T cell Foundation. E.S. was supported by the Stockholm County Council. apoptosis (10). Although being in the infancy, these studies reveal The datasets presented in this article have been submitted to the National Center for important roles for miRNAs in the biology of psoriasis. Biotechnology Information’s Gene Expression Omnibus (http://www.ncbi.nlm.nih. In this study, we identify a function for miR-31 in the context of gov/geo/) under accession number GSE41905. psoriasis. We show that specific inhibition of miR-31, a miRNA Address correspondence and reprint requests to Dr. Ning Xu, Molecular Dermatology overexpressed in psoriasis keratinocytes, suppresses NF-kBsig- Research Group, Centre for Molecular Medicine, L8:02, Department of Medicine, Karolinska Institute, SE-17176 Stockholm, Sweden. E-mail address: [email protected] naling and the production of IL-1b, CXCL1, CXCL5, and CXCL8/ The online version of this article contains supplemental material. IL-8. Serine/threonine kinase 40 (STK40), a negative modulator of Abbreviations used in this article: GSEA, gene set enrichment analysis; K5, keratin 5; NF-kB signaling, was identified as a direct target for miR-31. LNA, locked nucleic acid; miRNA, microRNA; qRT-PCR, quantitative real-time Furthermore, we identify TGF-b1, a cytokine highly expressed in PCR; siRNA, small interfering RNA; STK40, serine/threonine kinase 40; Treg, psoriasis epidermis, as a potent regulator of miR-31 expression in regulatory T cell; 39-UTR, 39-untranslated region; WT, wild-type. keratinocytes in vitro and in vivo. Taken together, our results Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 suggest that suppressing miR-31 in psoriasis skin may alleviate www.jimmunol.org/cgi/doi/10.4049/jimmunol.1202695 2 miR-31 IN PSORIASIS inflammation by interfering with the cross-talk between kerati- 2100 Bioanalyzer and Nanodrop ND-1000. One hundred nanograms of nocytes and immune cells. total RNA was used to prepare cDNA following the Affymetrix 39IVT Express Kit labeling protocol. Standardized array processing procedures recommended by Affymetrix including hybridization, fluidics processing, Materials and Methods and scanning were used. Genes showing at least 1.2-fold regulation, and Patients p , 0.05 was considered to be differentially expressed. Gene set enrich- ment analysis (GSEA) was performed using public software from Broad Four-millimeter punch biopsies were taken, after informed consent, from Institute (14, 15). The data discussed in this publication have been de- nonlesional (n = 20) and lesional skin (n = 43) of patients with moderate or posited in the National Center for Biotechnology Information’s Gene severe chronic plaque psoriasis and from noninflamed, nonirritated skin of Expression Omnibus (16) and are accessible through GEO Series ac- healthy individuals (n = 35). The psoriasis patients had not received sys- cession number GSE41905 (http://www.ncbi.nlm.nih.gov/geo/query/acc. temic immunosuppressive
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