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The chemotherapeutic drug carboplatin affects macrophage responses to LPS and LPS tolerance via epigenetic modifications

ABSTRACT: Following re-exposure to lipopolysaccharide (LPS), macrophages exhibit an immunosuppressive state known as LPS tolerance, which is characterized by repressed proinflammatory cytokine production. LPS-induced tolerance in macrophages is mediated in part by epigenetic changes. Carboplatin, an anticancer chemotherapeutic drug, exerts its effect by inhibiting DNA replication and transcription, as well as through epigenetic modifications. Through an unbiased screen, we found that carboplatin rescued TNF-α and IL-6 production in LPS-tolerant macrophages. Transcriptomic analysis and gene set enrichment analyses revealed that p53 was one of the most significantly upregulated hallmarks in both LPS-primed and LPS-tolerant macrophages in the presence of carboplatin, while E2F and G2/M were the most negatively regulated hallmarks. Heterochromatin protein 1 (HP1-α), which is associated with gene silencing, was significantly reduced in carboplatin-treated LPS-tolerant macrophages at the mRNA and protein levels. Dynamic changes in the mRNA level of genes encoding H3K9me3 methyltransferases, setdb2, kdm4d, and suv39h1 were induced in the presence of carboplatin in LPS-tolerant macrophages. Taken together, we provide evidence that carboplatin treatment interferes with proinflammatory cytokine production during the acute LPS response and LPS tolerance in macrophages, possibly via H3K9me3 modification.

SUBMITTER: Boonmee A

PROVIDER: S-EPMC8566489 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBleomycin, etoposide and cisplatin (BEP) are three chemotherapeutic agents widely used individually or in combination with each other or other chemotherapeutic agents in the treatment of various cancers. These chemotherapeutic agents are cytotoxic; hence, along with killing cancerous cells, they also damage stem cell pools in the body, which causes various negative effects on patients. The epigenetic changes due to the individual action of BEP on stem cells are largely unknown.MethodsHuman amniotic fluid stem cells (hAFSCs) were treated with our in-vitro standardized dosages of BEP individually, for seven days. The cells were harvested after the treatment and extraction of DNA and RNA were performed. Real-time PCR and flow cytometry were conducted for cell markers analysis. The global DNA methylation was quantified using 5mC specific kit and promoter and CpG methylation % through bisulfite conversion and pyrosequencing. Micro- RNAs (miRNAs) were quantified with real-time qPCR.ResultsThe cytotoxic nature of BEP was observed even at low dosages throughout the experiment. We also investigated the change in the expression of various pluripotent and germline markers and found a significant change in the properties of the cells after the treatments. The methylation of DNA at global, promoter and individual CpG levels largely get fluctuated due to the BEP treatment. Several tested miRNAs showed differential expression. No positive correlation between mRNA and protein expression was observed for some markers.ConclusionCytotoxic chemotherapeutic agents such as BEP were found to alter stem cell properties of hAFSCs. Different methylation profiles change dynamically, which may explain such changes in cellular properties. Data also suggests that the fate of hAFSCs after treatment may depend upon the interplay between the miRNAs. Finally, our results demonstrate that hAFSCs might prove to be a suitable in-vitro model of stem cells to predict genetic and epigenetic modification due to the action of various drugs.

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The chemotherapeutic drug carboplatin affects macrophage responses to LPS and LPS tolerance via epigenetic modifications

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