Glucose and TNF enhance expression of TNF and IL1B, and histone H3 acetylation and K4/K36 methylation, in juvenile macrophage cells

Honma, Kenji; Machida, Chie; Mochizuki, Kazuki; Goda, Toshinao

doi:10.1016/j.gene.2020.100034

Cited by 10 publications

(7 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, the TNF family and hyperglycemia was correlated and the genetic expression of TNF was maximized in GMSC and the same results have been seen in macrophages in 2020 [ 33 ]. Our study showed significant up regulation of TNF family members, such as TNFRSF1A, TNFSF10, LTA and more.…”

Section: Discussionsupporting

confidence: 83%

Effect of glucose mediated oxidative stress on apoptotic gene expression in gingival mesenchymal stem cells

et al. 2021

View full text Add to dashboard Cite

Background Diabetes is a common disease that causes gingival and periodontal problems. Stem cells isolated from dental sources are an emerging area of research with a potential to facilitate regenerative medicine. The stem cells retain the property of self-renewal and the ones isolated from dental sources are mainly multipotent mesenchymal stem cells that have the ability to self-renew as well as differentiation towards multiple lineages. Objectives We aimed to isolate and characterize gingival mesenchymal stem cells by pluripotency markers and investigated the effect of oxidative stress on growth kinetics and apoptotic gene expression of gingival cells exposed to glucose mediated oxidative stress. Methods In this study, we isolated gingival mesenchymal stem cells from gingiva. This was followed by morphologic analysis using inverted phase contrast microscopy and molecular profiling of these cells for the mRNA expression of specific genes. The isolated cells were cultured till passage 3 and then exposed to oxidative stress (high glucose concentration). We measured the apoptotic gene expression and compared their growth kinetics. Results The results showed that oxidative stress produced by glucose reduced growth kinetics and increased apoptotic gene expression in gingival mesenchymal stem cells. According to the genetic results, glucose activated TNF family to initiate apoptosis. Conclusion In conclusion, the present study demonstrated that high glucose obliterated cellular proliferation testified by evaluating growth kinetics and induced apoptotic gene expression in gingival mesenchymal stem cells. This initiated extrinsic apoptotic pathway mediated by TNF family. Therefore, in diabetes oral health condition is compromised and periodontal disease is common.

show abstract

Section: Discussionsupporting

confidence: 83%

Effect of glucose mediated oxidative stress on apoptotic gene expression in gingival mesenchymal stem cells

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Thinking of macrophages collectively as a specialized tissue whose job is not to proliferate in response immunostimulatory PAMPs/DAMPs (which can be thought of as “growth factors”), but rather to produce massive amounts of proinflammatory mRNAs, proteins, lipids, etc., it is logical that glucose availability, glucose utilization, and acetyl-CoA levels would be tightly linked to proinflammatory transcriptional programs in these cells, as they can only engage said programs if the requisite fuel is present. Indeed, myeloid cells are responsive to glucose concentrations, with high glucose being sufficient to upregulate proinflammatory gene histone acetylation and transcription ( 65, 66 ). Our work demonstrates CoA, not a nutrient itself, but rather a key facilitator of glucose utilization that routes glucose carbons into metabolites required for activation of proinflammatory genes, is sufficient to activate proinflammatory transcription programs, as long as some level of TLR-dependent “growth factor” signaling is present to promote glucose uptake and glycolytic oxidation.…”

Section: Discussionmentioning

confidence: 99%

Coenzyme A governs proinflammatory macrophage metabolism

Timblin

Tharp

Hoeve

et al. 2022

Preprint

View full text Add to dashboard Cite

The magnitude and duration of Toll-like receptor (TLR)-dependent macrophage proinflammatory responses are tightly regulated. Chronic TLR signaling drives tolerance, an immunosuppressed state of innate immune memory. Understanding of this regulation is incomplete. Here, we demonstrate that direct Coenzyme A (CoA) supplementation both reverses tolerance, and enhances TLR-dependent macrophage proinflammatory responses. Synergizing with TLR-driven glycolysis, CoA enhances glucose entry into the mitochondrial TCA cycle, fueling acetyl-CoA and citrate biosynthesis for epigenetic activation of proinflammatory gene transcription. CoA unlocks tumor-associated macrophage (TAM)-dependent TLR agonist anti-tumor activity in breast cancer, and promotes macrophage restriction of the intracellular bacterial pathogen Legionella pneumophila. Our findings identify CoA-dependent mitochondrial glucose utilization, and not aerobic glycolysis, as the key metabolic flux supporting TLR-dependent macrophage proinflammatory responses. Moreover, they show tolerance is a plastic state amenable to reversal by CoA, which re-routes glucose to restore requisite metabolic support of said responses, reversing myeloid immunosuppression in cancer and infection.

show abstract

“…Additionally, macrophages cultured in high-glucose conditions display increased expressions of cytokine genes and decreased H3K9me3 levels when compared with cells incubated in a normal glucose culture [68]. Methylation of H3K36 has also been found to be related to inflammatory functions and transcription of proinflammatory genes [39][40][41]. Our data suggest that while the expressions of unmodified histone H3 proteins and inflammatory marker proteins such as CXCL10 and CCR1 are probably regulated independently from each other by pro-and antiinflammatory agents, the subcellular localization of this protein and its methylated forms could be affected by both pro-and antiinflammatory agents through yet unidentified mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we investigated the relationships among (a) KYNA and its analog SZR104, (b) the inflammatory mechanisms that gives rise to epigenetic changes via histone methylations, and (c) the intracellular localizations of unmethylated and methylated histones in microglial cells. Besides the inflammatory markers CXCL10 and CCR1, we quantitatively analyzed the levels of unmodified core histone H3 and histone H3 lys methylations at the H3K9me3 and H3K36me2 sites (Table S2), marks that are considered contrary in regulating gene expression [37,38] and also involved in immunomodulation [39][40][41][42], using western blots and multicolor light microscopic immunofluorescence. As far as we know, our approach for studying KYNA and its brain-penetrable analog SZR104, with regard to epigenetics and neuroinflammation, is unique in the literature.…”

Section: Introductionmentioning

confidence: 99%

Kynurenic Acid and Its Analog SZR104 Exhibit Strong Antiinflammatory Effects and Alter the Intracellular Distribution and Methylation Patterns of H3 Histones in Immunochallenged Microglia-Enriched Cultures of Newborn Rat Brains

Szabó

Lajkó

Dulka

et al. 2022

IJMS

View full text Add to dashboard Cite

Kynurenic acid (KYNA) is implicated in antiinflammatory processes in the brain through several cellular and molecular targets, among which microglia-related mechanisms are of paramount importance. In this study, we describe the effects of KYNA and one of its analogs, the brain-penetrable SZR104 (N-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-hydroxyquinoline-2-carboxamide), on the intracellular distribution and methylation patterns of histone H3 in immunochallenged microglia cultures. Microglia-enriched secondary cultures made from newborn rat forebrains were immunochallenged with lipopolysaccharide (LPS). The protein levels of selected inflammatory markers C–X–C motif chemokine ligand 10 (CXCL10) and C–C motif chemokine receptor 1 (CCR1), histone H3, and posttranslational modifications of histone H3 lys methylation sites (H3K9me3 and H3K36me2, marks typically associated with opposite effects on gene expression) were analyzed using quantitative fluorescent immunocytochemistry and western blots in control or LPS-treated cultures with or without KYNA or SZR104. KYNA and SZR104 reduced levels of the inflammatory marker proteins CXCL10 and CCR1 after LPS-treatment. Moreover, KYNA and SZR104 favorably affected histone methylation patterns as H3K9me3 and H3K36me2 immunoreactivities, and histone H3 protein levels returned toward control values after LPS treatment. The cytoplasmic translocation of H3K9me3 from the nucleus indicated inflammatory distress, a process that could be inhibited by KYNA and SZR104. Thus, KYNA signaling and metabolism, and especially brain-penetrable KYNA analogs such as SZR104, could be key targets in the pathway that connects chromatin structure and epigenetic mechanisms with functional consequences that affect neuroinflammation and perhaps neurodegeneration.

show abstract

Glucose and TNF enhance expression of TNF and IL1B, and histone H3 acetylation and K4/K36 methylation, in juvenile macrophage cells

Cited by 10 publications

References 40 publications

Effect of glucose mediated oxidative stress on apoptotic gene expression in gingival mesenchymal stem cells

Effect of glucose mediated oxidative stress on apoptotic gene expression in gingival mesenchymal stem cells

Coenzyme A governs proinflammatory macrophage metabolism

Kynurenic Acid and Its Analog SZR104 Exhibit Strong Antiinflammatory Effects and Alter the Intracellular Distribution and Methylation Patterns of H3 Histones in Immunochallenged Microglia-Enriched Cultures of Newborn Rat Brains

Contact Info

Product

Resources

About