Abstract
The interaction between the immune system and epithelial cells is tightly regulated. Aberrations of this balance may result in inflammatory diseases such as psoriasis, inflammatory bowel disease and rheumatoid arthritis. IL-22 is produced by Th17, Th22 and Th1 cells. Putative targets for IL-22 are cells in the skin, kidney, digestive and respiratory systems. The highest expression of IL-22 receptor is found in the skin. IL-22 plays an important role in the pathogenesis of T cell-mediated inflammatory diseases such as psoriasis, inflammatory bowel disease and rheumatoid arthritis. Recently, we found that miR-197 is down regulated in psoriatic lesions. In the present work we show that miR-197 over expression inhibits keratinocytes proliferation induced by IL-22 and keratinocytes migration. In addition, we found that IL-22 activates miR-197 expression through the binding of phosphorylated STAT3 to sequences in the putative promoter of miR-197. Finally we found that IL-22 receptor subunit IL22RA1 is a direct target of miR-197. Hence, we identified a novel feedback loop controlling IL-22 signaling, in which IL-22 induces miR-197, which in turn, negatively regulates IL-22 receptor and attenuates the biological outcome of such signaling. Regulation of this pathway may be important in inflammatory skin disorders such a psoriasis and in wound healing.
Highlights
Micro-RNAs are small non-coding RNAs with important roles in post-transcriptional gene expression regulation
Expressing miR197 HaCaT cells were chosen as a model system, rather than primary human KC (PHK), due to the fact that miRNA mimics are diluted and lost during cell division
In PHK that were grown in high Ca++ medium, conditions known to drive keratinocytes towards differentiation [33], MiR-197 expression was elevated compared to its expression in cells grown in low Ca++ medium (Fig. 1f)
Summary
Micro-RNAs (miRNAs) are small non-coding RNAs with important roles in post-transcriptional gene expression regulation. We found that miR-99a targets IGF-1R [4], a major player in KC proliferation and differentiation [12] Despite these findings, many functions of miRNAs in skin are still largely unknown and their role in the pathogenesis of skin disorders is even less understood. We and others previously showed that miR-197 is significantly down regulated in psoriatic lesions compared to normal skin [4,27]. We previously showed by qRT- PCR, that the expression of mir-197 was ,3-fold lower in psoriatic skin as compared to normal skin. This was confirmed by In situ hybridizations [4]. The present study is aimed to investigate its biologic roles in KC and in skin biology
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