Chemokine Production in Keratinocytes via and Modulates Inflammatory Cytokine and MicroRNA-31 Is Overexpressed in Psoriasis

نویسندگان

  • Andor Pivarcsi
  • Enikö Sonkoly
  • Xiao-Jing Wang
  • Cecilia Söderberg-Nauclér
  • Mona Ståhle
  • Ning Xu
  • Florian Meisgen
  • Lynn M. Butler
  • Gangwen Han
چکیده

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 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-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. P soriasis is a common chronic inflammatory skin disease, which affects 2–3% of the population. It is a lifelong disease with spontaneous remissions and exacerbations that are severely detrimental to the patients' quality of life (1). Psoriasis skin lesions are typically characterized by keratinocyte hyperproliferation and aberrant differentiation, increased vascu-larity in the dermis, and infiltration of inflammatory cells, such as macrophages, neutrophils, and lymphocytes into the dermis and epidermis (1). There is a close interdependence between kerati-nocytes and immune cells in psoriatic skin: the cytokines and chemokines secreted by keratinocytes, such as IL-1b, TNF-a, CXCL1/growth-related oncogene-a, CXCL5/epithelial-derived neutrophil-activating peptide 78, and CXCL8/IL-8 activate and attract immune cells to migrate into epidermis and dermis; immune cell–derived cytokines, in turn, act on keratinocytes to increase the expression of inflammatory genes, promote keratinocyte proliferation , and impair keratinocyte differentiation (reviewed in Ref. 1). microRNAs (miRNAs) are ∼ 22nt long single-stranded noncoding RNAs that mediate posttranscriptional silencing by binding with partial complementarity to the 39-untranslated region (39-UTR) of target mRNA (2). miRNAs are estimated to regulate ∼60% of all protein-coding genes in humans and …

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تاریخ انتشار 2012