Dataset Information

MK8617 inhibits M1 macrophage polarization and inflammation via the HIF-1α/GYS1/UDPG/P2Y₁₄ pathway.

ABSTRACT:

Background

Nonresolving inflammation is a major driver of disease and needs to be taken seriously. Hypoxia-inducible factor (HIF) is closely associated with inflammation. Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs), as stabilizers of HIF, have recently been reported to have the ability to block inflammation. We used MK8617, a novel HIF-PHI, to study its effect on macrophage inflammation and to explore its possible mechanisms.

Methods

Cell viability after MK8617 and lipopolysaccharide (LPS) addition was assessed by Cell Counting Kit-8 (CCK8) to find the appropriate drug concentration. MK8617 pretreated or unpretreated cells were then stimulated with LPS to induce macrophage polarization and inflammation. Inflammatory indicators in cells were assessed by real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR), western blot (WB) and immunofluorescence (IF). The level of uridine diphosphate glucose (UDPG) in the cell supernatant was measured by ELISA. Purinergic G protein-coupled receptor P2Y₁₄, as well as hypoxia-inducible factor-1α (HIF-1α) and glycogen synthase 1 (GYS1) were detected by qRT-PCR and WB. After UDPG inhibition with glycogen phosphorylase inhibitor (GPI) or knockdown of HIF-1α and GYS1 with lentivirus, P2Y₁₄ and inflammatory indexes of macrophages were detected by qRT-PCR and WB.

Results

MK8617 reduced LPS-induced release of pro-inflammatory factors as well as UDPG secretion and P2Y₁₄ expression. UDPG upregulated P2Y₁₄ and inflammatory indicators, while inhibition of UDPG suppressed LPS-induced inflammation. In addition, HIF-1α directly regulated GYS1, which encoded glycogen synthase, an enzyme that mediated the synthesis of glycogen by UDPG, thereby affecting UDPG secretion. Knockdown of HIF-1α and GYS1 disrupted the anti-inflammatory effect of MK8617.

Conclusions

Our study demonstrated the role of MK8617 in macrophage inflammation and revealed that its mechanism of action may be related to the HIF-1α/GYS1/UDPG/P2Y₁₄ pathway, providing new therapeutic ideas for the study of inflammation.

SUBMITTER: Qian L

PROVIDER: S-EPMC10317019 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

MK8617 inhibits M1 macrophage polarization and inflammation <i>via</i> the HIF-1α/GYS1/UDPG/P2Y<sub>14</sub> pathway.

Qian Lingling L Chen Xiao-Qin XQ Kong Deyang D Wang Gaoyuan G Cao Yun Y Xiao Yingchun Y Cao Jing-Yuan JY Zou Chunbo C

PeerJ 20230630

<h4>Background</h4>Nonresolving inflammation is a major driver of disease and needs to be taken seriously. Hypoxia-inducible factor (HIF) is closely associated with inflammation. Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs), as stabilizers of HIF, have recently been reported to have the ability to block inflammation. We used MK8617, a novel HIF-PHI, to study its effect on macrophage inflammation and to explore its possible mechanisms.<h4>Methods</h4>Cell viability after MK86 ...[more]

PMID: 37404479

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Dataset Information

MK8617 inhibits M1 macrophage polarization and inflammation via the HIF-1α/GYS1/UDPG/P2Y₁₄ pathway.

Background

Methods

Results

Conclusions

Publications

MK8617 inhibits M1 macrophage polarization and inflammation <i>via</i> the HIF-1α/GYS1/UDPG/P2Y<sub>14</sub> pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

MK8617 inhibits M1 macrophage polarization and inflammation via the HIF-1α/GYS1/UDPG/P2Y14 pathway.

Background

Methods

Results

Conclusions

Publications

MK8617 inhibits M1 macrophage polarization and inflammation <i>via</i> the HIF-1α/GYS1/UDPG/P2Y<sub>14</sub> pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

MK8617 inhibits M1 macrophage polarization and inflammation via the HIF-1α/GYS1/UDPG/P2Y₁₄ pathway.