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Open AccessArticle

Inhibitor of Hyaluronic Acid Synthesis 4-Methylumbelliferone as an Anti-Inflammatory Modulator of LPS-Mediated Astrocyte Responses

1
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
2
SREC PFUR, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia
3
Faculty of Bioengineering and Bioinformatics, Moscow Lomonosov State University, 119234 Moscow, Russia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(21), 8203; https://doi.org/10.3390/ijms21218203
Received: 11 October 2020 / Revised: 25 October 2020 / Accepted: 30 October 2020 / Published: 2 November 2020
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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. View Full-Text
Keywords: astrocytes; 4-methylumbelliferone (4-MU); cyclooxygenase (COX); hyaluronic acid; interleukin 10 (IL-10); interleukin 6 (IL-6); neuroinflammation; oxylipins; toll-like receptors (TLRs) astrocytes; 4-methylumbelliferone (4-MU); cyclooxygenase (COX); hyaluronic acid; interleukin 10 (IL-10); interleukin 6 (IL-6); neuroinflammation; oxylipins; toll-like receptors (TLRs)
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MDPI and ACS Style

Chistyakov, D.V.; Nikolskaya, A.I.; Goriainov, S.V.; Astakhova, A.A.; Sergeeva, M.G. Inhibitor of Hyaluronic Acid Synthesis 4-Methylumbelliferone as an Anti-Inflammatory Modulator of LPS-Mediated Astrocyte Responses. Int. J. Mol. Sci. 2020, 21, 8203. https://doi.org/10.3390/ijms21218203

AMA Style

Chistyakov DV, Nikolskaya AI, Goriainov SV, Astakhova AA, Sergeeva MG. Inhibitor of Hyaluronic Acid Synthesis 4-Methylumbelliferone as an Anti-Inflammatory Modulator of LPS-Mediated Astrocyte Responses. International Journal of Molecular Sciences. 2020; 21(21):8203. https://doi.org/10.3390/ijms21218203

Chicago/Turabian Style

Chistyakov, Dmitry V.; Nikolskaya, Arina I.; Goriainov, Sergei V.; Astakhova, Alina A.; Sergeeva, Marina G. 2020. "Inhibitor of Hyaluronic Acid Synthesis 4-Methylumbelliferone as an Anti-Inflammatory Modulator of LPS-Mediated Astrocyte Responses" Int. J. Mol. Sci. 21, no. 21: 8203. https://doi.org/10.3390/ijms21218203

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