Positive-Negative Feedback Loop between Mir-197 and IL-17A Signaling in Human Keratinocytes
Autor: | Riad Kassem, Dror Avni, Einat Elharrar, Moti Harats, Yechezkel Sidi, Moamen Masalha, Raya Leibowitz-Amit, Galya Lerman |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Effector Applied Mathematics Immunology Promoter Biology Molecular biology Computer Science Applications Chromatin 03 medical and health sciences 030104 developmental biology Histone Computational Theory and Mathematics biology.protein Ectopic expression Signal transduction Binding site Receptor Molecular Biology |
Zdroj: | Immunome Research. 12 |
ISSN: | 1745-7580 |
Popis: | Psoriasis is a chronic inflammatory skin disorder which results from pathological interactions between activated immunocytes and keratinocytes. Recent studies implicated the role of IL-17 and IL-22, secreted from Th17 and Th22 in the generation and propagation of the psoriatic plaque. Previously, we and others have shown that the expression of miR-197 is significantly decreased in psoriatic lesions. We further showed that miR-197 targets IL-22RA1 and that ectopic expression of miR-197 prevent IL-22 induced proliferation and migration of keratinocytes. Since the 3'UTR of the IL17RA subunit mRNA contains a putative binding site for miR-197, our aim was to expand our understanding of the miRNA-mediated crosstalk between immunocytes and keratinocytes by studying the effect of miR-197 expression on IL-17A signaling pathway. Luciferase reporter assays along with Western blot analysis revealed that miR-197 directly targets the 3'UTR of IL17RA. Furthermore, ectopic expression of miR-197 led to a significant decrease in IL-17A-induced expression of CCL20, a known downstream effector of IL-17A. Interestingly, the addition of IL-17A to keratinocytes led to a rapid and transient increase in the expression of miR-197. Chromatin immuno-precipitation assays showed that keratinocytes' treatment with IL-17 leads to C/EBP binding to the promoter region of miR-197, and that the expression level of miR-197 is directly proportional to the extent of C/EBP binding to the promoter. Moreover, following treatment with IL-17A, the histone acetylation pattern at the miR-197 promoter turns to become characteristic of transcribed chromatin. Taken together, our results suggest that a positive-negative feedback loop exists between IL-17A and miR-197 in keratinocytes; the cytokine induces the binding of C/EBPα to miR-197 promoter sequences, enhances miR-197 expression that negatively attenuates IL-17 receptor and decreases the input along the IL-17A pathway. Our work suggests that in psoriasis, decreased expression of miR-197 may prevent the miR-197-induced attenuation of the IL-17 cascade, leading to its over-activity. |
Databáze: | OpenAIRE |
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