title: MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40.
abstract: 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-κB-driven promoter luciferase activity and the basal and TNF-α-induced production of IL-1β, CXCL1/growth-related oncogene-α, CXCL5/epithelial-derived neutrophil-activating peptide 78, and CXCL8/IL-8 in human primary keratinocytes. Moreover, interference with 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-κB 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-β1, a cytokine highly expressed in psoriasis epidermis, upregulated miR-31 expression in keratinocytes in vitro and in vivo. Collectively, our findings suggest that overexpression 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.
authors.affiliation: Molecular Dermatology Research Group, Unit of Dermatology and Venereology, Department of Medicine, Karolinska Institute, SE-17176 Stockholm, Sweden. ning.xu@ki.se
authors.forename: Ning
authors.initials: N
authors.lastname: Xu
authors.forename: Florian
authors.initials: F
authors.lastname: Meisgen
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Butler
authors.forename: Gangwen
authors.initials: G
authors.lastname: Han
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.forename: Cecilia
authors.initials: C
authors.lastname: Söderberg-Nauclér
authors.forename: Mona
authors.initials: M
authors.lastname: Ståhle
authors.forename: Andor
authors.initials: A
authors.lastname: Pivarcsi
authors.forename: Enikö
authors.initials: E
authors.lastname: Sonkoly
mesh_terms: D018925:Chemokines / Q000096:biosynthesis; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011565:Psoriasis / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D034622:RNA Interference; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; C534864:STK40 protein, human