2. Academic Validation
  3. Topoisomerase 2 inhibitor etoposide promotes interleukin-10 production in LPS-induced macrophages via upregulating transcription factor Maf and activating PI3K/Akt pathway

Topoisomerase 2 inhibitor etoposide promotes interleukin-10 production in LPS-induced macrophages via upregulating transcription factor Maf and activating PI3K/Akt pathway

  • Int Immunopharmacol. 2021 Dec;101(Pt A):108264. doi: 10.1016/j.intimp.2021.108264.
Jiaxin Zhang 1,  Haoxin Zhao 2,  Yuan Feng 3,  Xin Xu 2,  Yili Yang 4,  Pengxia Zhang 5,  Zhiliang Lu 6,  Tao Zhang 7
Affiliations

Affiliations

  • 1 Department of Immunology, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China; Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China; Key Laboratory of Microecology-immune Regulatory Network and Related Diseases of Heilongjiang Province, Jiamusi, Heilongjiang, China.
  • 2 Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.
  • 3 Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China; Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou, China.
  • 4 China Regional Research Center, International Centre for Genetic Engineering and Biotechnology, Taizhou, China.
  • 5 Department of Immunology, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China; Key Laboratory of Microecology-immune Regulatory Network and Related Diseases of Heilongjiang Province, Jiamusi, Heilongjiang, China. Electronic address: pengxiaz@163.com.
  • 6 Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou, China. Electronic address: Zhiliang.lu@xjtlu.edu.cn.
  • 7 Department of Immunology, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China; Key Laboratory of Microecology-immune Regulatory Network and Related Diseases of Heilongjiang Province, Jiamusi, Heilongjiang, China. Electronic address: ztlzy1971@163.com.
PMID: 34715493 DOI: 10.1016/j.intimp.2021.108264
Abstract

Topoisomerase (TOP) inhibitors were commonly used as chemotherapeutic agents in the treatment of cancers. In our present study, we found that etoposide (ETO), a Topoisomerase 2 (TOP2) inhibitor, upregulated the production of Interleukin 10 (IL-10) in lipopolysaccharide (LPS)-stimulated macrophages. Besides, other TOP2 inhibitors including doxorubicin hydrochloride (DOX) and teniposide (TEN) were also able to augment IL-10 production. Meanwhile, the expression levels of pro-inflammatory factors, for example IL-6 and TNF-α, were also decreased accordingly by the treatment of the TOP2 inhibitors. Of note, ETO facilitated IL-10 secretion, which might be regulated by transcription factor Maf via PI3K/Akt pathway, as pharmaceutic blockage of kinase PI3K or Akt attenuated ETO-induced Maf and IL-10 expression. Further, in LPS-induced mice sepsis model, the enhanced generation of IL-10 was observed in ETO-treated mice, whereas pro-inflammatory cytokines were decreased, which significantly reduced the mortality of mice from LPS-induced lethal cytokine storm. Taken together, these results indicated that ETO may exhibit an anti-inflammatory role by upregulating the alteration of transcription factor Maf and promoting subsequential IL-10 secretion via PI3K/Akt pathway in LPS-induced macrophages. Therefore, ETO may serve as a potential anti-inflammatory agent and employed to severe pro-inflammatory diseases including COVID-19.

Keywords

Etoposide; IL-10; Inflammation; Maf; PI3K/Akt; TOP II inhibtor.

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