| 1. |
- Meisgen, Florian, et al.
(författare)
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MiR-21 is up-regulated in psoriasis and suppresses T cell apoptosis.
- 2012
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Ingår i: Experimental dermatology. - : Wiley. - 0906-6705 .- 1600-0625. ; 21:4, s. 312-4
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs are short non-coding RNAs that regulate gene expression. Previously, in a genome-wide screen, we found deregulation of microRNA expression in psoriasis skin. MicroRNA-21 (miR-21) is one of the microRNAs significantly up-regulated in psoriasis skin lesions. To identify the cell type responsible for the increased miR-21 level, we compared expression of miR-21 in epidermal cells and dermal T cells between psoriasis and healthy skin and found elevated levels of miR-21 in psoriasis in both cell types. In cultured T cells, expression of miR-21 increased markedly upon activation. To explore the function of miR-21 in primary human T helper cells, we inhibited miR-21 using a tiny seed-targeting LNA-anti-miR. Specific inhibition of miR-21 increased the apoptosis rate of activated T cells. Our results suggest that miR-21 suppresses apoptosis in activated T cells, and thus, overexpression of miR-21 may contribute to T cell-derived psoriatic skin inflammation.
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| 2. |
- Sonkoly, Enikö, et al.
(författare)
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MicroRNAs : novel regulators involved in the pathogenesis of psoriasis?
- 2007
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 2:7
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs are a recently discovered class of posttranscriptional regulators of gene expression with critical functions in health and disease. Psoriasis is the most prevalent chronic inflammatory skin disease in adults, with a substantial negative impact on the patients' quality of life. Here we show for the first time that psoriasis-affected skin has a specific microRNA expression profile when compared with healthy human skin or with another chronic inflammatory skin disease, atopic eczema. Among the psoriasis-specific microRNAs, we identified leukocyte-derived microRNAs and one keratinocyte-derived microRNA, miR-203. In a panel of 21 different human organs and tissues, miR-203 showed a highly skin-specific expression profile. Among the cellular constituents of the skin, it was exclusively expressed by keratinocytes. The up-regulation of miR-203 in psoriatic plaques was concurrent with the down-regulation of an evolutionary conserved target of miR-203, suppressor of cytokine signaling 3 (SOCS-3), which is involved in inflammatory responses and keratinocyte functions. Our results suggest that microRNA deregulation is involved in the pathogenesis of psoriasis and contributes to the dysfunction of the cross talk between resident and infiltrating cells. Taken together, a new layer of regulatory mechanisms is involved in the pathogenesis of chronic inflammatory skin diseases.
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| 3. |
- Sonkoly, Enikö, et al.
(författare)
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MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte-associated antigen 4.
- 2010
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 126:3, s. 581-9.e1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: MicroRNAs (miRNAs) are short noncoding RNAs that suppress gene expression at the posttranscriptional level. Atopic dermatitis is a common chronic inflammatory skin disease characterized by the presence of activated T cells within the skin.OBJECTIVE: We sought to explore the role of miRNAs in the pathogenesis of atopic dermatitis.METHODS: Global miRNA expression in healthy and lesional skin of patients with atopic dermatitis was compared by using TaqMan MicroRNA Low Density Arrays. miR-155 expression in tissues and cells was quantified by means of quantitative real-time PCR. The cellular localization of miR-155 was analyzed by means of in situ hybridization. The regulation of cytotoxic T lymphocyte-associated antigen (CTLA-4) by miR-155 was investigated by using luciferase reporter assays and flow cytometry. CTLA-4 expression and functional assays were performed on T(H) cells overexpressing miR-155.RESULTS: miR-155 was one of the highest-ranked upregulated miRNAs in patients with atopic dermatitis. In the skin miR-155 was predominantly expressed in infiltrating immune cells. miR-155 was upregulated during T-cell differentiation/activation and was markedly induced by T-cell activators in PBMCs in vitro and by superantigens and allergens in the skin in vivo. CTLA-4, an important negative regulator of T-cell activation, was identified as a direct target of miR-155. Overexpression of miR-155 in T(H) cells resulted in decreased CTLA-4 levels accompanied by an increased proliferative response.CONCLUSION: miR-155 is significantly overexpressed in patients with atopic dermatitis and might contribute to chronic skin inflammation by increasing the proliferative response of T(H) cells through the downregulation of CTLA-4.
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| 4. |
- Sonkoly, Enikö, et al.
(författare)
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Protein kinase C-dependent upregulation of miR-203 induces the differentiation of human keratinocytes
- 2010
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 130:1, s. 124-134
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Tidskriftsartikel (refereegranskat)abstract
- Terminal differentiation of keratinocytes is a multistep process that requires a coordinated program of gene expression. We aimed to explore the possible involvement of a previously unreported class of non-coding RNA genes, microRNAs (miRNAs) in keratinocyte differentiation by using miRNA expression profiling. Out of 365 miRNAs tested, 7 showed significant change between keratinocytes cultured in low or high calcium concentration. The highest-ranked upregulated gene was miR-203, whose expression was significantly upregulated in response to calcium and other inducers of keratinocyte differentiation such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and vitamin D(3). Differentiation-induced upregulation of miR-203 expression was blocked by treatment with specific inhibitors of protein kinase C (PKC), GF109203X, and Ro31-8220. Moreover, our results showed that the activator protein-1 (AP-1) proteins c-Jun and JunB regulate miR-203 expression in keratinocytes. In contrast to inducers of keratinocyte differentiation, epidermal growth factor and keratinocyte growth factor suppressed miR-203 expression in keratinocytes below the basal level. Overexpression of miR-203 in keratinocytes resulted in enhanced differentiation, whereas inhibition of miR-203 suppressed calcium-induced terminal differentiation as judged by involucrin expression. These results suggest that upregulation of miR-203 in human keratinocytes is required for their differentiation and is dependent on the activation of the PKC/AP-1 pathway.
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| 5. |
- Wei, Tianling, et al.
(författare)
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Detergents with different chemical properties induce variable degree of cytotoxicity and mRNA expression of lipid-metabolizing enzymes and differentiation markers in cultured keratinocytes
- 2006
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Ingår i: Toxicology in Vitro. - : Elsevier BV. - 0887-2333 .- 1879-3177. ; 126, s. 21-21
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Tidskriftsartikel (refereegranskat)abstract
- The knowledge how detergents with different chemical properties influence epidermal keratinocytes is sparse. In the present study, the effects of five detergents were examined with respect to cell-toxicity and mRNA expression of key-enzymes in barrier lipid production and keratinocyte differentiation markers. First, the LD(50) for each detergent were determined. Secondly, keratinocytes were exposed to sub-toxic concentrations and the mRNA expression was analysed by real-time PCR after 24 h exposure to the detergents. SLS and CAPB induced a concentration-dependent increase in the expression of enzymes producing cholesterol and ceramides, while transcripts of enzymes producing fatty acids were unaffected. SLES and cocoglucoside increased the expression of certain enzymes involved in cholesterol and fatty acid synthesis while sodium cocoamphoacetate (SCAA) stimulated expression of transcripts involved in fatty acid synthesis. The expression of differentiation markers were increased by SLS, SLES and CAPB, while SCAA and cocoglucoside exhibited no effect. The present findings show that detergents have variable effects on lipid synthesis and keratinocyte differentiation, which could partly explain their barrier destruction potential in vivo.
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| 6. |
- Wei, Tianling, et al.
(författare)
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Interleukin-8 is regulated by miR-203 at the posttranscriptional level in primary human keratinocytes.
- 2013
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Ingår i: EJD. European journal of dermatology. - 1167-1122 .- 1952-4013.
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Tidskriftsartikel (refereegranskat)abstract
- Background: MicroRNAs are important posttranscriptional regulators of gene expression. MiR-203 is a miRNA preferentially expressed in the skin, and an important regulator of keratinocyte differentiation. MiR-203 has been implicated in skin diseases, in particular in psoriasis in which it is overexpressed, and in basal cell carcinoma where it acts as a tumor suppressor miRNA. Objectives: To identify novel targets for miR-203 that may be relevant in skin physiology and diseases. Materials & Methods: Bioinformatics was used to identify putative miR-203 targets among genes expressed in keratinocytes. Interleukin-8 (IL-8) gene expression and concentration in keratinocyte medium was measured by quantitative real-time PCR and ELISA, respectively. For miRNA overexpression, resting or TNF-α-treated primary human keratinocytes were transfected with synthetic precursor of miR-203, or scramble miRNA precursors using Lipofectamine 2000. 3'UTR luciferase reporter experiments were performed to prove the direct miRNA:mRNA interaction. Site-specific mutagenesis was used to mutate the predicted miR-203 binding sites in the 3'UTR of IL-8 gene. Results: Bioinformatic analysis indentified two putative miR-203 binding sites in the 3'UTR of IL-8. MiR-203 suppressed IL-8 mRNA and protein expression in primary human keratinocytes both under resting conditions and after TNF-α treatment. Overexpression of miR-203 suppressed the luciferase activity of a reporter gene fused with the IL-8 3'UTR. The suppressive effect was abolished when the predicted binding sites of miR-203 on IL-8 3'UTR were mutated. Conclusion: We identify IL-8 as a novel target of miR-203 for posttranscriptional suppression. These findings may have relevance in diseases in which miR-203 and IL-8 expression are deregulated.
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| 7. |
- Wei, Tianling, et al.
(författare)
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The expression of microRNA-203 during human skin morphogenesis.
- 2010
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Ingår i: Experimental dermatology. - : Wiley. - 0906-6705 .- 1600-0625. ; 19:9, s. 854-6
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs are small, non-coding RNAs that regulate gene expression post-transcriptionally and play important roles in various biological processes. We previously identified miR-203 as a skin- and keratinocyte-specific microRNA. Moreover, miR-203 has been implicated in repressing 'stemness' in epidermal progenitors. Here, we investigate the expression of miR-203 and two of its targets, p63 and suppressor of cytokine signalling-3, during human skin morphogenesis. MiR-203 in situ hybridization was performed on sections of human foetal skin ranging from 14 to 22 weeks' gestation and adult skin. MiR-203 was barely detectable at 14 weeks. Its expression became prominent from week 17 and was most pronounced in the suprabasal layers of the epidermis, while p63 and SOCS-3 were preferentially expressed in the basal layer. Differentiation markers such as involucrin and filaggrin were expressed mainly in the suprabasal layers of epidermis, similar to miR-203. Our results support the involvement of miR-203 in skin morphogenesis.
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| 8. |
- Wei, Tianling
(författare)
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The role of miR-203 in keratinocyte biology and psoriasis
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Psoriasis is one of the most common chronic inflammatory skin diseases. It is a life long suffering disease affecting approximately 2 to 3% of the population in Scandinavia. Significant progress has been made to understand the cellular immunology and biology of psoriasis. However, the cause is still unclear and we still lack a cure for this common and enigmatic disease. MicroRNAs (miRNAs) are 18-22 nucleotides non-coding RNAs that regulate gene expression at the post-transcriptional level by targeting mRNAs for translational suppression or degradation. Extensive studies in the last few years showed that miRNAs play important roles in physiological processes and diseases. Before our investigation, no connection had been established between miRNAs and psoriasis. The general aim of this thesis was to investigate the involvement of miRNAs in the pathogenesis of psoriasis and skin/keratinocyte biology. In paper I, we showed for the first time that psoriasis-affected skin has a specific microRNA expression profile compared with healthy human skin or with another chronic inflammatory skin disease, atopic eczema. Among the psoriasis-associated microRNAs, we identified one skin and keratinocyte-specific microRNA, miR-203. The up-regulation of miR-203 in psoriatic plaques was concurrent with the down-regulation of one of its evolutionary conserved target, suppressor of cytokine signaling 3 (SOCS-3), which is involved in inflammatory responses and keratinocyte functions. This paper unveiled the involvement of microRNAs in inflammatory skin diseases. In paper II, we particularly examined the role of miR-203 in keratinocyte differentiation. Out of 365 miRNAs tested, miR-203 was the most upregulated miRNA during keratinocyte differentiation. Furthermore, we found that upregulation of miR-203 is required for keratinocyte differentiation and is dependent on the activation of the PKC/AP-1 pathway. In paper III, we explored the expression of miR-203 during human skin morphogenesis. MiR-203 is barely detectable at 14 weeks of estimated gestation age (EGA). Its expression became prominent from week 17 and was most pronounced in the suprabasal layers of the epidermis. The direct targets of miR-203, p63 and SOCS-3, were preferentially expressed in the basal layer. Our results suggest miR-203 is involved in the regulation of human foetal skin development and provide a basis for further studies to investigate the role of miR-203 in this process. In paper IV, we studied the role of miR-203 in NF-κB signaling in keratinocytes. We found that overexpression of miR-203 in human primary keratinocytes suppressed NF- κB activity by 1) suppressing downstream genes in NF-κB pathway; 2) preventing the nuclear translocation of p65 and repressing NF-κB-driven promoter luciferase activity. The results suggested that miR-203 plays a potential role in keeping skin homeostasis and controlling inflammation by modulating NF-κB signaling. In conclusion, our data in the thesis suggest that miR-203 plays a role as ‘safety guard’ in skin by regulating inflammation-, differentiation-, proliferation- and morphogenesis- associated processes.
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| 9. |
- Xu, Ning, et al.
(författare)
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MiR-125b, a microRNA downregulated in psoriasis, modulates keratinocyte proliferation by targeting FGFR2.
- 2011
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 131:7, s. 1521-9
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRNAs) are short, single-stranded, noncoding RNAs that play important roles in the regulation of gene expression. We previously identified a characteristic miRNA expression profile in psoriasis, distinct from that of healthy skin. One of the most downregulated miRNAs in psoriasis skin was microRNA-125b (miR-125b). In this study, we aimed to identify the potential role(s) of miR-125b in psoriasis pathogenesis. In situ hybridization results showed that the major cell type responsible for decreased miR-125b levels in psoriasis lesions was the keratinocyte. Overexpression of miR-125b in primary human keratinocytes suppressed proliferation and induced the expression of several known differentiation markers. Conversely, inhibition of endogenous miR-125b promoted cell proliferation and delayed differentiation. Fibroblast growth factor receptor 2 (FGFR2) was identified as one of the direct targets for suppression by miR-125b by luciferase reporter assay. The expression of miR-125b and FGFR2 was inversely correlated in both transfected keratinocytes and in psoriatic skin. Knocking down FGFR2 expression by siRNA suppressed keratinocyte proliferation, but did not enhance differentiation. Altogether, our results demonstrate a role for miR-125b in the regulation of keratinocyte proliferation and differentiation, partially through the regulation of FGFR2. Loss of miR-125b in psoriasis skin may contribute to hyperproliferation and aberrant differentiation of keratinocytes.
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