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Regulation of cytokines by small RNAs during skin inflammation

Bak RO, Mikkelsen JG - J. Biomed. Sci. (2010)

Bottom Line: In skin, an inflammatory response is mediated by cytokines and an entwined network of cellular communication between T-cells and epidermal keratinocytes.Cytokines are heavily regulated at the transcriptional level, but emerging evidence suggests that regulatory mechanisms that operate after transcription play a key role in balancing the production of cytokines.The proposed linkage between mRNA decay mediated by AU-rich elements and miRNA association is described and discussed as a possible general feature of cytokine regulation in skin.

Affiliation: Department of Human Genetics, University of Aarhus, DK-8000 Aarhus C, Denmark.

ABSTRACT

Intercellular signaling by cytokines is a vital feature of the innate immune system. In skin, an inflammatory response is mediated by cytokines and an entwined network of cellular communication between T-cells and epidermal keratinocytes. Dysregulated cytokine production, orchestrated by activated T-cells homing to the skin, is believed to be the main cause of psoriasis, a common inflammatory skin disorder. Cytokines are heavily regulated at the transcriptional level, but emerging evidence suggests that regulatory mechanisms that operate after transcription play a key role in balancing the production of cytokines. Herein, we review the nature of cytokine signaling in psoriasis with particular emphasis on regulation by mRNA destabilizing elements and the potential targeting of cytokine-encoding mRNAs by miRNAs. The proposed linkage between mRNA decay mediated by AU-rich elements and miRNA association is described and discussed as a possible general feature of cytokine regulation in skin. Moreover, we describe the latest attempts to therapeutically target cytokines at the RNA level in psoriasis by exploiting the cellular RNA interference machinery. The applicability of cytokine-encoding mRNAs as future clinical drug targets is evaluated, and advances and obstacles related to topical administration of RNA-based drugs targeting the cytokine circuit in psoriasis are described.

Overview of RNA interference pathways. The RNA interference pathway is active in endogenous regulation of gene expression, in which pri-miRNAs are transcribed from the genome and processed in several steps ultimately leading to a mature miRNA which is loaded into the effector protein complex called RISC from where the guide strand of the miRNA guides RISC to mRNAs by sequence-specific target recognition. Depending on the degree of sequence similarity, RISC facilitates either translational suppression or mRNA degradation. The pathway can be exploited for sequence-specific down-regulation of a gene, by transfection of synthetic siRNAs or intracellular expression of shRNAs which are both efficiently processed by the RNAi machinery and enter the RNAi pathway.
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Figure 4: Overview of RNA interference pathways. The RNA interference pathway is active in endogenous regulation of gene expression, in which pri-miRNAs are transcribed from the genome and processed in several steps ultimately leading to a mature miRNA which is loaded into the effector protein complex called RISC from where the guide strand of the miRNA guides RISC to mRNAs by sequence-specific target recognition. Depending on the degree of sequence similarity, RISC facilitates either translational suppression or mRNA degradation. The pathway can be exploited for sequence-specific down-regulation of a gene, by transfection of synthetic siRNAs or intracellular expression of shRNAs which are both efficiently processed by the RNAi machinery and enter the RNAi pathway.

Mentions: An extensive and important group of non-coding RNAs (ncRNAs) appeared with the discovery of miRNAs. More than 700 different miRNAs have been identified in humans and the pathway by which miRNAs exert sequence-specific gene silencing has been elucidated, though numerous questions still remain unanswered. The miRNA pathway was found to converge with the RNA interference (RNAi) pathway [90] by which double-stranded RNA with sequence homology to the mRNA of a particular gene induce post-transcriptional silencing of that gene (Figure 4). The RNAi pathway was first suggested to play a crucial role in a very efficient antiviral mechanism against double-stranded RNA viruses but now, with the discovery of miRNAs, also represent a key path for tuning endogenous gene expression by post-transcriptional regulation.

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Regulation of cytokines by small RNAs during skin inflammation

Bak RO, Mikkelsen JG - J. Biomed. Sci. (2010)

Overview of RNA interference pathways. The RNA interference pathway is active in endogenous regulation of gene expression, in which pri-miRNAs are transcribed from the genome and processed in several steps ultimately leading to a mature miRNA which is loaded into the effector protein complex called RISC from where the guide strand of the miRNA guides RISC to mRNAs by sequence-specific target recognition. Depending on the degree of sequence similarity, RISC facilitates either translational suppression or mRNA degradation. The pathway can be exploited for sequence-specific down-regulation of a gene, by transfection of synthetic siRNAs or intracellular expression of shRNAs which are both efficiently processed by the RNAi machinery and enter the RNAi pathway.
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Figure 4: Overview of RNA interference pathways. The RNA interference pathway is active in endogenous regulation of gene expression, in which pri-miRNAs are transcribed from the genome and processed in several steps ultimately leading to a mature miRNA which is loaded into the effector protein complex called RISC from where the guide strand of the miRNA guides RISC to mRNAs by sequence-specific target recognition. Depending on the degree of sequence similarity, RISC facilitates either translational suppression or mRNA degradation. The pathway can be exploited for sequence-specific down-regulation of a gene, by transfection of synthetic siRNAs or intracellular expression of shRNAs which are both efficiently processed by the RNAi machinery and enter the RNAi pathway.
Mentions: An extensive and important group of non-coding RNAs (ncRNAs) appeared with the discovery of miRNAs. More than 700 different miRNAs have been identified in humans and the pathway by which miRNAs exert sequence-specific gene silencing has been elucidated, though numerous questions still remain unanswered. The miRNA pathway was found to converge with the RNA interference (RNAi) pathway [90] by which double-stranded RNA with sequence homology to the mRNA of a particular gene induce post-transcriptional silencing of that gene (Figure 4). The RNAi pathway was first suggested to play a crucial role in a very efficient antiviral mechanism against double-stranded RNA viruses but now, with the discovery of miRNAs, also represent a key path for tuning endogenous gene expression by post-transcriptional regulation.

Bottom Line: In skin, an inflammatory response is mediated by cytokines and an entwined network of cellular communication between T-cells and epidermal keratinocytes.Cytokines are heavily regulated at the transcriptional level, but emerging evidence suggests that regulatory mechanisms that operate after transcription play a key role in balancing the production of cytokines.The proposed linkage between mRNA decay mediated by AU-rich elements and miRNA association is described and discussed as a possible general feature of cytokine regulation in skin.

Affiliation: Department of Human Genetics, University of Aarhus, DK-8000 Aarhus C, Denmark.

ABSTRACT

Background: Intercellular signaling by cytokines is a vital feature of the innate immune system. In skin, an inflammatory response is mediated by cytokines and an entwined network of cellular communication between T-cells and epidermal keratinocytes. Dysregulated cytokine production, orchestrated by activated T-cells homing to the skin, is believed to be the main cause of psoriasis, a common inflammatory skin disorder. Cytokines are heavily regulated at the transcriptional level, but emerging evidence suggests that regulatory mechanisms that operate after transcription play a key role in balancing the production of cytokines. Herein, we review the nature of cytokine signaling in psoriasis with particular emphasis on regulation by mRNA destabilizing elements and the potential targeting of cytokine-encoding mRNAs by miRNAs. The proposed linkage between mRNA decay mediated by AU-rich elements and miRNA association is described and discussed as a possible general feature of cytokine regulation in skin. Moreover, we describe the latest attempts to therapeutically target cytokines at the RNA level in psoriasis by exploiting the cellular RNA interference machinery. The applicability of cytokine-encoding mRNAs as future clinical drug targets is evaluated, and advances and obstacles related to topical administration of RNA-based drugs targeting the cytokine circuit in psoriasis are described.

View Similar Images In: Results  - Collection
View Article: Pubmed Central - HTML -  PubMed
Show All Figures - Show MeSH
getmorefigures.php?pmc=2905360&rFormat=json&query=null&req=5