Abstract
Matrix metalloproteinases (MMPs) are important for the pathogenesis of psoriasis and other autoimmune disorders. In the extracellular matrix, accumulation of proinflammatory cytokines, such as interleukin 17A (IL-17A), leads to induction of several MMPs, including MMP1. MMPs change the composition and other properties of the extracellular matrix. These changes facilitate tissue remodeling and promote the development of psoriatic plaques. The aim of this study was to explore how MMP1 silencing might influence the biological effects of IL-17A on migration and proliferation of human epidermal keratinocytes and the expression of genes involved in their division and differentiation. The experiments were performed with MMP1-deficient and control epidermal keratinocytes, HaCaT-MMP1 and HaCaT-KTR, respectively. Cell proliferation and migration were assessed by comparative analysis of the growth curves and scratch assay, respectively. To quantify cell migration, representative areas of cell cultures were photographed at the indicated time points and compared to each other. Changes in gene expression were analyzed by real-time PCR. The obtained results demonstrated that MMP1 silencing in the cells treated with IL-17A resulted in downregulation of MMP9 and -12, FOSL1, CCNA2, IVL, KRT14 and -17 as well as upregulation of MMP2, CCND1 and LOR. Moreover, MMP1 silencing led to a decrease in cell proliferation and an impairment of cell migration. Thus, MMP1-deficiency in epidermal keratinocytes can be beneficial for psoriasis patients that experience an accumulation of IL-17 in lesional skin. Knocking MMP1 down could influence migration and proliferation of epidermal keratinocytes in vivo, as well as help to control the expression of MMP1, -2, -9 и -12, CCNA2, CCND1, KRT14 and -17 that are crucial for the pathogenesis of psoriasis.
Highlights
How to cite this article: Mogulevtseva J.A., Mezentsev A.V., Bruskin S.A
Influence of matrix metalloproteinase 1 (MMP1) silencing on gene expression Culturing HaCaT-KTR and HaCaT-MMP1 cells in the presence of interleukin 17A (IL-17A) resulted in a differential expression of matrix metalloproteinases, cytokeratins, proliferation markers and terminal differentiation markers of epidermal keratinocytes (Fig. 1)
The exposure of HaCaT-KTR cells to IL-17A led to upregulation of MMP9 and MMP12 (11.15 ± 1.67 and 7.58 ± 1.14, respectively) and downregulation of MMP2 (0.37 ± 0.05)
Summary
How to cite this article: Mogulevtseva J.A., Mezentsev A.V., Bruskin S.A. RNAi-mediated silencing of matrix metalloproteinase 1 in epidermal keratinocytes influences the biological effects of interleukin 17A. Целью данной работы было исследовать влияние РНК-интерференции MMP1 на биологические эффекты ИЛ-17A, такие как способность данного цитокина стимулировать миграцию и пролиферацию эпидермальных кератиноцитов человека, а также регулировать экспрессию генов, которые играют важную роль в процессе дифференцировки данного типа клеток. В клетках, обработанных ИЛ-17A, РНК-интерференция MMP1 приводит к уменьшению экспрессии MMP9 и MMP12, FOSL1, CCNA2, IVL, KRT14 и KRT17, а также к увеличению экспрессии MMP2, CCND1 и LOR. «Нокдаун» ММП1 позволяет воздействовать на пролиферацию и миграцию клеток, а также контролировать экспрессию важных для патогенеза болезни генов (MMP1, MMP2, MMP9 и MMP12, CCNA2, CCND1, KRT14 и KRT17). IL-17A contributes to the inflammatory response by inducing the chemokines CCL20, CXCL1, CXCL2, and CXCL8 Their secretion to the extracellular matrix promotes the migration of activated immune cells to lesional epidermis. The accumulation of immune cells in lesional skin stabilizes there the inflammatory process (Seo et al, 2017)
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