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Artesunate protects immunosuppression mice induced by glucocorticoids via enhancing pro-inflammatory cytokines release and bacterial clearance.

ABSTRACT: Glucocorticoids are commonly used in clinic, but the immunosuppression seriously hinders their usage. Herein, immunomodulatory effect of artesunate (AS) on hydrocortisone (HC)-induced immunosuppression was investigated. HC-induced immunosuppression mice (HC mice) were established by intramuscular administration with HC (20 mg/kg) once a day for 5 consecutive days. The results showed HC mice challenged with Escherichia coli on the sixth day presented a lower ability to clear bacteria, decreased TNF-? in blood, decreased spleen index and thymus index. Significantly, AS (20 mg/kg) treatment not only enhanced the ability of HC mice to clear bacteria, but also increased spleen index, the levels of pro-inflammatory cytokines from 78.7 ± 12.1 ng/ml (TNF-?) and 48.7 ± 8.6 pg/ml (IL-6) to 174.0 ± 90.5 ng/ml and 783.3 ± 90.5 pg/ml, number of white blood cells in blood, and sIgA in colon. Subsequently, HC-induced immunosuppression peritoneal macrophages model (HC cells) was established via addition of HC (0.5 ?g/ml) for 0.5 h, and then LPS (100 ng/ml) was added to clarify the functional status of the cells. The results showed HC inhibited TNF-? and IL-6 mRNA expressions and their release, but AS (2.5 ?g/ml) could increase TNF-? and IL-6 mRNA expressions and their release. AS inhibited GILZ mRNA up-regulated by HC and increases TLR4/NF-?B p65 expressions down-regulated by HC. Our findings revealed that AS's effect is closely related to the improvement of the TLR4/NF-?B signal transduction pathway via inhibiting the up-regulation of GILZ mRNA, demonstrating AS does possess immunomodulatory effects and is worth further investigation in the future.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7546998 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Artesunate protects immunosuppression mice induced by glucocorticoids via enhancing pro-inflammatory cytokines release and bacterial clearance.

Wang Yan Y Liao Mengling M Zhang Yu Y Deng Fei F Luo Jing J Wang Nuoyan N Liu Min M Ao Lin L Fang Qimei Q Wang Qingchun Q Zhou Hong H

European journal of pharmacology 20201010

Glucocorticoids are commonly used in clinic, but the immunosuppression seriously hinders their usage. Herein, immunomodulatory effect of artesunate (AS) on hydrocortisone (HC)-induced immunosuppression was investigated. HC-induced immunosuppression mice (HC mice) were established by intramuscular administration with HC (20 mg/kg) once a day for 5 consecutive days. The results showed HC mice challenged with Escherichia coli on the sixth day presented a lower ability to clear bacteria, decreased T ...[more]

PMID: 33045197

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Project description:Background and purposeImmunosuppression is the predominant cause of mortality for sepsis because of failure to eradicate pathogens. No effective and specific drugs capable of reversing immunosuppression are clinically available. Evidences implicate the involvement of the vitamin D receptor (NR1I1) in sepsis-induced immunosuppression. The anti-malarial artesunate was investigated to determine action on sepsis-induced immunosuppression.Experimental approachThe effect of artesunate on sepsis-induced immunosuppression was investigated in mice and human and mice cell lines. Bioinformatics predicted vitamin D receptor as a candidate target for artesunate, which was then identified using PCR and immunoblotting. Vdr, Atg16l1 and NF-κB p65 were modified to investigate artesunate 's effect on pro-inflammatory cytokines release, bacterial clearance and autophagy activities in sepsis-induced immunosuppression.Key resultsArtesunate significantly reduced the mortality of caecal ligation and puncture (CLP)-induced sepsis immunosuppression mice challenged with Pseudomonas aeruginosa and enhanced pro-inflammatory cytokine release and bacterial clearance to reverse sepsis-induced immunosuppression in vivo and in vitro. Mechanistically, artesunate interacted with vitamin D receptor, inhibiting its nuclear translocation, which influenced ATG16L1 transcription and subsequent autophagy activity. Artesunate inhibited the physical interaction between vitamin D receptor and NF-κB p65 in LPS-tolerant macrophages and then promoted the nuclear translocation of NF-κB p65, which activated the transcription of NF-κB p65 target genes such as pro-inflammatory cytokines.Conclusion and implicationsOur findings provide evidence that artesunate interacted with vitamin D receptor to reverse sepsis-induced immunosuppression in an autophagy and NF-κB-dependent manner, highlighting a novel approach for sepsis treatment and drug repurposing of artesunate has a bidirectional immunomodulator.

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Artesunate protects immunosuppression mice induced by glucocorticoids via enhancing pro-inflammatory cytokines release and bacterial clearance.

Publications

Artesunate protects immunosuppression mice induced by glucocorticoids via enhancing pro-inflammatory cytokines release and bacterial clearance.

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