vestnik-bio-msuВестник Московского университета. Серия 16. БиологияVestnik Moskovskogo universiteta. Seriya 16. Biologiya0137-0952Lomonosov Moscow State University, School of Biologyvestnik-bio-msu-1165Research ArticleОРИГИНАЛЬНОЕ ИССЛЕДОВАНИЕRESEARCH ARTICLEВлияние антиоксидантов на продукцию хемокина MCP-1 клетками линии EA.hy926 в ответ на IL-6Effect of antioxidants on the production of MCP-1 chemokine by EA.hy926 cells in response to IL-6https://orcid.org/0000-0002-3902-7812ЧеломбитькоМ. А.ChelombitkoM. A.

Челомбитько Мария Александровна – канд. биол. наук, ст. науч. сотр. отд. мат. методов в биологии НИИ ФХБ им. А.Н. Белозерского

119992, г. Москва, Ленинские горы, д. 1, стр. 40Тел.: 8-495-939-03-38

Belozersky Institute of Physico-Chemical Biology

1–40 Leninskie gory, Moscow, 119992

chelombitko@mail.bio.msu.ruhttps://orcid.org/0000-0002-9025-3794ГалкинИ. И.GalkinI. I.

Галкин Иван Ильич – канд. биол. наук, ст. науч. сотр. отд. мат. методов в биологии НИИ ФХБ им. А.Н. Белозерского

119992, г. Москва, Ленинские горы, д. 1, стр. 40Тел.: 8-495-939-03-38

Belozersky Institute of Physico-Chemical Biology

1–40 Leninskie gory, Moscow, 119992

ddeathseller@gmail.comhttps://orcid.org/0000-0002-4963-9054ПлетюшкинаО. Ю.PletjushkinaO. Yu.

Плетюшкина Ольга Юрьевна – канд. биол. наук, ст. науч. сотр. отд. мат. методов в биологии НИИ ФХБ им. А.Н. Белозерского

119992, г. Москва, Ленинские горы, д. 1, стр. 40Тел.: 8-495-939-03-38

Belozersky Institute of Physico-Chemical Biology

1–40 Leninskie gory, Moscow, 119992

pletjush@genebee.msu.ruhttps://orcid.org/0000-0001-5337-4346ЗиновкинР. А.ZinovkinR. A.

Зиновкин Роман Алексеевич – канд. биол. наук, зав. лабораторией электронного транспорта отдела молекулярной энергетики микроорганизмов НИИ ФХБ им. А.Н. Белозерского

119992, г. Москва, Ленинские горы, д. 1, стр. 40Тел.: 8-495-939-03-38

Belozersky Institute of Physico-Chemical Biology

1–40 Leninskie gory, Moscow, 119992

roman.zinovkin@gmail.comhttps://orcid.org/0000-0002-7521-7736ПоповаЕ. Н.PopovaE. N.

Попова Екатерина Николаевна – канд. биол. наук, ст. науч. сотр. отд. мат. методов в биологии НИИ ФХБ им. А.Н. Белозерского

119992, г. Москва, Ленинские горы, д. 1, стр. 40Тел.: 8-495-939-03-38

Belozersky Institute of Physico-Chemical Biology

1–40 Leninskie gory, Moscow, 119992

k_popova_ch@mail.ruМосковский государственный университет имени М.В. ЛомоносоваРоссияLomonosov Moscow State UniversityRussian Federation202220082022773201208Copyright © Челомбитько М.А., Галкин И.И., Плетюшкина О.Ю., Зиновкин Р.А., Попова Е.Н., 20222022Челомбитько М.А., Галкин И.И., Плетюшкина О.Ю., Зиновкин Р.А., Попова Е.Н.Chelombitko M.A., Galkin I.I., Pletjushkina O.Y., Zinovkin R.A., Popova E.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestnik-bio-msu.elpub.ru/jour/article/view/1165

Повышенный уровень интерлейкина-6 (IL-6) в крови является биомаркером цитокинового шторма, вызванного различными заболеваниями, и способствует плохим исходам этих заболеваний, в том числе COVID-19. Одной из основных мишеней патологического действия IL-6 являются эндотелиальные клетки сосудов, которые IL-6 активирует за счет транс-сигнального пути – формирования рецепторного комплекса IL-6/sIL-6Ra/gp130 и последующей индукции сигнального пути JAK/STAT3, а также в ряде случаев PI3K/AKT и MEK/ERK. Ранее было показано, в том числе нами, что активные формы кислорода (АФК), в том числе митохондриального происхождения (мито-АФК), способствуют индукции экспрессии IL-6 в эндотелии главным образом за счет усиления активации транскрипционного фактора NF-kB. Более того, мы показали, что митохондриально-направленный антиоксидант SkQ1 (10-(6’-пластохинонил)децилтрифенилфосфоний) предотвращает гибель мышей, у которых цитокиновый шторм был вызван внутривенным введением фактора некроза опухолей (TNF) в летальной дозе, а также экспрессию NF-kB-зависимых генов, в том числе цитокина IL-6 и хемокина MCP-1 в аортах этих животных. В текущей работе мы проверили гипотезу об участии мито-АФК в передаче сигнала и экспрессии провоспалительных генов в эндотелиальных клетках, активированных IL-6. SkQ1 подавлял индуцированную IL-6 в комбинации с sIL-6-Ra экспрессию и секрецию хемокина МСР-1, но не экспрессию молекул адгезии ICAM1 в эндотелиальных клетках человека линии EA.hy926. Используя специфические ингибиторы, мы показали, что в этих клетках вызванная IL-6 экспрессия МСР-1 и ICAM-1 зависит от сигнального белка и активатора транскрипции STAT3 и в некоторых случаях – от киназ JNK, PI3K и MEK1/2, а также не зависит от киназы p38. В данной модели IL-6 вызывал быструю активацию STAT3 и значительно менее выраженную активацию ERK1/2, но не влиял на активацию Akt и JNK. SkQ1 частично подавлял активацию STAT3 и ERK1/2. Таким образом, мы показали, что SkQ1 подавляет не только NF-kB-зависимую экспрессию IL-6 и других провоспалительных генов, но и вызванную IL-6 активацию JAK/STAT3 и STAT3-зависимую экспрессию MCP-1. Это, вероятно, вносит вклад в общий противовоспалительный эффект SkQ1.

Elevated level of circulatory interleukin 6 (IL-6) is a biomarker for cytokine storm of various etiologies including COVID-19 and contributes to poor prognosis. Vascular endothelial cells are one of the main targets of pathological action of IL-6. IL-6 activates trans-signaling pathway via the formation of the IL-6/sIL-6Ra/gp130 receptor complex and subsequent activation of the JAK/STAT3 signaling pathway, and in some cases PI3K/AKT and MEK/ERK kinases. Previously, by our group and other researchers, it was shown that reactive oxygen species (ROS) including mitochondrial ROS (mito-ROS) contribute to the induction of IL-6 expression in the endothelium, mainly due to increased activation of the transcription factor NF-kB. We have also shown that the mitochondria-targeted antioxidant SkQ1 (plastoquinolyl-10(6’-decyltriphenyl) phosphonium) prevented tumor necrosis factor (TNF)-induced cytokine storm and death in mice. In the aortas of these animals, SkQ1 also prevented the increase in the expression of NF-kB-dependent genes, including the cytokine IL-6 and the chemokine MCP-1. In the current work, we have tested the hypothesis of mito-ROS involvement in the IL-6-signaling-mediated pro-inflammatory gene expression in endothelial cells. SkQ1 suppressed the expression and secretion of the MCP-1 chemokine, induced by IL-6 in combination with sIL-6-Ra, but not the expression of ICAM1 adhesion molecules in EA.hy926 human endothelial cells. Using specific inhibitors, we have shown that in EA.hy926 cells, IL-6-induced expression of MCP-1 and ICAM-1 depends on the signaling protein and transcription activator STAT3 and, in some cases, on JNK, PI3K, and MEK1/2 kinases and is independent of p38 kinase. In this model, IL-6 induced rapid STAT3 activation while ERK1/2 activation was less pronounced, and there was no IL-6 effect on Akt and JNK activation. SkQ1 partially suppressed STAT3 and ERK1/2 activation. Thus, we have shown that SkQ1 suppresses not only NF-kB-dependent expression of IL-6 and other proinflammatory genes, but also IL-6-induced activation of JAK/STAT3 and STAT3-dependent expression of MCP-1, which probably contributes to the overall therapeutic effect of SkQ1.

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