Regulation of cytokines by small RNAs during skin inflammation.
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.
Bak
Rasmus O
RO
Department of Human Genetics, University of Aarhus, DK-8000 Aarhus C, Denmark.
Mikkelsen
Jacob G
JG
D016207:Cytokines / Q000276:immunology* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D035683:MicroRNAs / Q000378:metabolism*; D011565:Psoriasis / Q000276:immunology* / Q000628:therapy; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*
D016207:Cytokines; D035683:MicroRNAs; D012333:RNA, Messenger