Regulation of pro-inflammatory cytokines TNFα and IL24 by microRNA-203 in primary keratinocytes.
Cutaneous homeostasis and innate immunity is procured by a complex circuitry of intercellular cytokine signaling. MicroRNAs are important posttranscriptional regulators of keratinocyte gene expression and assist in modulating the fine balance between cell proliferation and differentiation in skin. A characteristic microRNA profile in inflammatory skin suggests putative functions of microRNAs in perturbed cytokine production and signaling during chronic inflammatory skin conditions such as psoriasis. It remains unclear, however, why certain microRNAs are aberrantly expressed during skin inflammation and if they serve pro- and/or anti-inflammatory functions. In this report, we focus on cytokine regulation by microRNA-203 (miR-203), which is highly abundant in keratinocytes and upregulated in psoriatic lesions. By screening a panel of cytokines that are upregulated in psoriatic skin for regulation by miR-203, we identify the genes encoding the pro-inflammatory cytokines TNFα and IL24 as direct targets of miR-203. Studies of miR-203 overexpression, inhibition, and mutagenesis validate posttranscriptional regulation of TNFα and IL24 by miR-203 in cell lines and primary keratinocytes. Our findings suggest that miR-203 serves to fine-tune cytokine signaling and may dampen skin immune responses by repressing key pro-inflammatory cytokines.
Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark.
Maria Nascimento
MN
Primo
Rasmus O
RO
Bak
Beatrice
B
Schibler
Jacob Giehm
JG
Mikkelsen
D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D011565:Psoriasis / Q000235:genetics / Q000276:immunology; D012323:RNA Processing, Post-Transcriptional; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D000099180:Interleukin-24
D007378:Interleukins; D035683:MicroRNAs; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D000099180:Interleukin-24; C546703:MIRN203 microRNA, human; C473085:SOCS6 protein, human