vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ18.378vavilov-1545Research ArticleМОЛЕКУЛЯРНАЯ И КЛЕТОЧНАЯ БИОЛОГИЯMOLECULAR AND CELL BIOLOGYОСОБЕННОСТИ ПРОТЕКАНИЯ РНК-ИНТЕРФЕРЕНЦИИ МАТРИКСНОЙ МЕТАЛЛОПРОТЕИНАЗЫ 1 В ЭПИДЕРМАЛЬНЫХ КЕРАТИНОЦИТАХ, ОБРАБОТАННЫХ ИНТЕРЛЕЙКИНОМ 17ARNAI-MEDIATED SILENCING OF MATRIX METALLOPROTEINASE 1 IN EPIDERMAL KERATINOCYTES INFLUENCES THE BIOLOGICAL EFFECTS OF INTERLEUKIN 17AМогулевцеваЮ. А.MogulevtsevaJ. A.

Москва

МезенцевА. В.MezentsevA. V.

Москва

Moscow

mesentsev@vigg.ruБрускинС. А.BruskinS. A.

Москва

Moscow

Российский государственный аграрный университет – МСХА им. К.А. ТимирязеваРоссияRussian State Agrarian University – Moscow Timiryazev Agricultural AcademyRussian FederationИнститут общей генетики им. Н.И. Вавилова Российской академии наукРоссияN.I. Vavilov Institute of General Genetics RASRussian Federation201804072018224425432Copyright © Могулевцева Ю.А., Мезенцев А.В., Брускин С.А., 20182018Могулевцева Ю.А., Мезенцев А.В., Брускин С.А.Mogulevtseva J.A., Mezentsev A.V., Bruskin S.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/1545

Матриксные металлопротеиназы (ММП) играют важную роль в патогенезе псориаза, а также ряда других аутоиммунных заболеваний. Накопление интерлейкина 17A (ИЛ-17A) и других провоспалительных цитокинов в межклеточном матриксе приводит к индукции генов некоторых матриксных металлопротеиназ, в частности MMP1. Рост протеолитической активности в межклеточном матриксе меняет его состав и свойства, а также способствует структурной реорганизации пораженного болезнью участка кожи. Структурная реорганизация, в свою очередь, приводит к изменению внешнего облика кожных покровов и образованию псориатических бляшек. 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 так же регулировать экспрессию генов, которые играют важную роль в процессе дифференцировки данного типа клеток. В работе использовали иммортализованные эпидермальные кератиноциты с «нокдауном» MMP1 и без него – HaCaT-ММП1 и HaCaT-КТР соответственно. Для оценки пролиферации клеток сопоставляли кривые их роста. Миграцию клеток оценивали путем сравнения репрезентативных фотографических изображений, которые были получены через равные промежутки времени. Изменения в экспрессии генов анализировали методом ПЦР в режиме реального времени. Согласно полученным результатам, 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» MMP1 замедляет процесс миграции клеток и приводит к снижению скорости их пролиферации. Таким образом, проведенное нами исследование показало, что в присутствии ИЛ-17A РНК-интерференция MMP1 обладает потенциальным терапевтическим эффектом, который может быть использован при лечении псориаза. «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).

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.

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The authors declare that there are no conflicts of interest present.