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The chemokine CXCL9 exacerbates chemotherapy-induced acute intestinal damage through inhibition of mucosal restitution

Journal of Cancer Research and Clinical Oncology volume 141, pages 983–992 (2015)Cite this article

Abstract

Purpose

Acute intestinal damage induced by chemotherapeutic agent is often a dose-limiting factor in clinical cancer therapy. The aim of this study was to investigate the effect of chemokine CXCL9 on the intestinal damage after chemotherapy and explore the therapeutic potential of anti-CXCL9 agents.

Methods

In vitro cell proliferation assay was performed with a non-tumorigenic human epithelial cell line MCF10A. Multiple pathway analysis was carried out to explore the pathway that mediated the effect of CXCL9, and the corresponding downstream effector was identified with enzyme-linked immunosorbent assays. Chemotherapy-induced mouse model of intestinal mucositis was prepared by a single injection of the chemotherapeutic agent 5-fluorouracil (5-FU). In vivo expression of cxcl9 and its receptor cxcr3 in intestinal mucosa after chemotherapy was determined by quantitative real-time PCR. Therapeutic treatment with anti-CXCL9 antibodies was investigated to confirm the hypothesis that CXCL9 can contribute to the intestinal epithelium damage induced by chemotherapy.

Results

CXCL9 inhibited the proliferation of MCF10A cells by activating phosphorylation of p70 ribosomal S6 kinase (p70S6K), which further promotes the secretion of transforming growth factor beta (TGF-β) as the downstream effector. A blockade of phospho-p70S6K with inhibitor abolished the effect of CXCL9 on MCF10A cells and reduced the secretion of TGF-β. The expression levels of cxcl9 and cxcr3 were significantly up-regulated in intestinal mucosa after 5-FU injection. Neutralizing elevated CXCL9 with anti-CXCR9 antibodies successfully enhanced reconstitution of intestinal mucosa and improved the survival rate of mice that received high-dose chemotherapy.

Conclusions

CXCL9 inhibits the proliferation of epithelial cells via phosphorylation of p70S6K, resulting in the excretion of TGF-β as downstream mediator. CXCL9/CXCR3 interaction can exacerbate chemotherapeutic agent-induced intestinal damage, and anti-CXCL9 agents are potential novel therapeutic candidates for promoting mucosal restitution.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (grant number 81273576, 30801419, 30901873) and the German Academic Exchange Service and China Scholarship Council (Grant number A/09/90104). We would also like to thank Dr. Baier and Ms. Krohl at the Robert Koch Institute in Berlin, Germany, for their kind help in the technology of immunohistochemistry.

Conflict of interest

We declare no competing interests.

Author information

Affiliations

  1. Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China

    Huili Lu, Jiaxian Wang, Lei Han, Tao Sun & Jianwei Zhu

  2. Regeneromics Laboratory, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China

    Huili Lu, Shunyan Weng, Lan Qian, Mingyuan Wu & Wei Han

  3. Division of Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Hongyu Liu

  4. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Jiangsu, China

    Jiaqing Shen

  5. Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China

    Shunying Zhu & Yan Yu

  6. Institute for Haemostaseology and Transfusion Medicine, Klinikum Ludwigshafen, Ludwigshafen am Rhein, Germany

    Anja Moldenhauer

  7. Institute for Clinical Haemostaseology and Transfusion Medicine, Saarland University Medical Faculty, Homburg, Germany

    Anja Moldenhauer

Authors
  1. Huili Lu
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  2. Hongyu Liu
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  3. Jiaxian Wang
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  4. Jiaqing Shen
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  5. Shunyan Weng
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  6. Lei Han
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  7. Tao Sun
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  8. Lan Qian
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  9. Mingyuan Wu
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  10. Shunying Zhu
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  11. Yan Yu
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  12. Wei Han
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  13. Jianwei Zhu
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  14. Anja Moldenhauer
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Corresponding authors

Correspondence to Wei Han or Jianwei Zhu.

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Lu, H., Liu, H., Wang, J. et al. The chemokine CXCL9 exacerbates chemotherapy-induced acute intestinal damage through inhibition of mucosal restitution. J Cancer Res Clin Oncol 141, 983–992 (2015). https://doi.org/10.1007/s00432-014-1869-y

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  • DOI: https://doi.org/10.1007/s00432-014-1869-y

Keywords

  • CXCL9
  • Epithelial cell
  • Proliferation
  • Chemotherapy
  • Intestinal damage