Inhibitor of hyaluronic acid synthesis 4-methylumbelliferone as an anti-inflammatory modulator of lps-mediated astrocyte responses

Astrocytes are glial cells that play an important role in neuroinflammation. Astrocytes respond to many pro-inflammatory stimuli, including lipopolysaccharide (LPS), an agonist of Toll-like receptor 4 (TLR4). Regulatory specificities of inflammatory signaling pathways are still largely unknown due to the ectodermal origin of astrocytes. Recently, we have shown that hyaluronic acid (HA) may form part of astrocyte inflammatory responses. Therefore, we tested 4-methylumbelliferone (4-MU), a specific inhibitor of HA synthesis, as a possible regulator of LPS-mediated responses. Rat primary astrocytes were treated with LPS with and without 4-MU and gene expression levels of inflammatory (interleukins 1β, (IL-1β), 6, (IL-6), tumor necrosis factor alpha TNFα,) and resolution interleukin 10 (IL-10) markers were evaluated via real-time PCR and western blot. The release of cytokines and HA was determined by ELISA. Oxylipin profiles were measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. Our data show that 4-MU (i) has anti-inflammatory effects in the course of TLR4 activation, decreasing the cytokines level TNFα, IL-6 and IL-1β and increasing IL-10, (ii) downregulates prostaglandin synthesis but not via cyclooxygenases COX-1 and COX-2 pathways, (iii) modulates HA synthesis and decreases LPS-induced HA synthase mRNA expression (HAS-1, HAS-2) but does not have an influence on HAS-3, HYAL1 and HYAL2 mRNAs; (iv) the effects of 4-MU are predominantly revealed via JNK but not p38, ERK mitogen-activated protein kinases (MAPKs) or nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathways. For the first time, it is shown that 4-MU possesses the useful potential to regulate an inflammatory astrocyte response. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Авторы
Chistyakov D.V. 1, 3 , Nikolskaya A.I.2 , Goriainov S.V. 3 , Astakhova A.A.1 , Sergeeva M.G. 1
Издательство
MDPI AG
Номер выпуска
21
Язык
Английский
Страницы
1-16
Статус
Опубликовано
Номер
8203
Том
21
Год
2020
Организации
  • 1 Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119992, Russian Federation
  • 2 Faculty of Bioengineering and Bioinformatics, Moscow Lomonosov State University, Moscow, 119234, Russian Federation
  • 3 SREC PFUR, Peoples’ Friendship University of Russia (RUDN University), Moscow, 117198, Russian Federation
Ключевые слова
4-methylumbelliferone (4-MU); Astrocytes; Cyclooxygenase (COX); Hyaluronic acid; Interleukin 10 (IL-10); Interleukin 6 (IL-6); Neuroinflammation; Oxylipins; Toll-like receptors (TLRs)
Дата создания
20.04.2021
Дата изменения
20.04.2021
Постоянная ссылка
https://repository.rudn.ru/ru/records/article/record/72466/
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