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IL-1Ra Protects Hematopoietic Stem Cells from Chemotoxicity Through Quiescence Induction Via p53

29 Pages Posted: 22 Jan 2019 Sneak Peek Status: Under Review

See all articles by Hao Ye

Hao Ye

Shanghai Jiao Tong University (SJTU) - Laboratory of Regeneromics

Lan Qian

Shanghai Jiao Tong University (SJTU) - Laboratory of Regeneromics

Shunying Zhu

Shanghai Jiao Tong University (SJTU) - National Infrastructures of Translational Medicine

Shaorong Deng

Shanghai Jiao Tong University (SJTU) - Laboratory of Regeneromics

Xia Wang

Shanghai Jiao Tong University (SJTU) - Laboratory of Regeneromics

Jiang Zhu

Shanghai Jiao Tong University (SJTU) - Blood Research Institute

Gerald L. Chan

Peking University - Morningside Peking University Joint Laboratory in Integrative Pathobiology

Yan Yu

Shanghai Jiao Tong University (SJTU) - Shanghai Municipality Key Laboratory of Veterinary Biotechnology

Wei Han

Shanghai Jiao Tong University (SJTU) - Laboratory of Regeneromics

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Abstract

The protection of constantly proliferating gut epithelia and hematopoietic tissues from cytotoxicity could improve conventional chemotherapy efficacy and widen its therapeutic window. Previously, we reported that in mouse models, recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) protected both types of vulnerable tissues from chemotherapeutics. Here, we showed that rhIL-1Ra upregulated phosphorylated p38, p53, and p21, and induced transient hematopoietic stem cell (HSC) quiescence. Knockout of the alleles of IL-1RI, p53, or p21 and pharmacological inactivation of p38 mapped the rhIL-1Ra pathway in the induction of bone marrow (BM) quiescence. Therefore, rhIL-1Ra administration before but not after chemotherapy alleviated 5-FU-induced neutropenia. The rhIL-1Ra treatment did not affect cancer cell proliferation or chemosensitivity. We propose an IL-1/IL-1Ra pathway (IL-1RI → p38 → p53 → p21), which regulates HSC quiescence. The rhIL-1Ra may provide a new route for p53-based cyclotherapy, which spares normal cells and kills cancer cells in chemotherapy.

Keywords: IL-1Ra, hematopoietic stem cells, quiescence, neutropenia, cyclotherapy, chemotherapy, p53

Suggested Citation

Ye, Hao and Qian, Lan and Zhu, Shunying and Deng, Shaorong and Wang, Xia and Zhu, Jiang and Chan, Gerald L. and Yu, Yan and Han, Wei, IL-1Ra Protects Hematopoietic Stem Cells from Chemotoxicity Through Quiescence Induction Via p53 (January 19, 2019). Available at SSRN: https://ssrn.com/abstract=3318930 or http://dx.doi.org/10.2139/ssrn.3318930
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Hao Ye

Shanghai Jiao Tong University (SJTU) - Laboratory of Regeneromics

Shanghai 200030, Shanghai 200052
China

Lan Qian

Shanghai Jiao Tong University (SJTU) - Laboratory of Regeneromics

Shanghai 200030, Shanghai 200052
China

Shunying Zhu

Shanghai Jiao Tong University (SJTU) - National Infrastructures of Translational Medicine

Shanghai 200030, Shanghai 200052
China

Shaorong Deng

Shanghai Jiao Tong University (SJTU) - Laboratory of Regeneromics

Shanghai 200030, Shanghai 200052
China

Xia Wang

Shanghai Jiao Tong University (SJTU) - Laboratory of Regeneromics

Shanghai 200030, Shanghai 200052
China

Jiang Zhu

Shanghai Jiao Tong University (SJTU) - Blood Research Institute

Shanghai 200030, Shanghai 200052
China

Gerald L. Chan

Peking University - Morningside Peking University Joint Laboratory in Integrative Pathobiology

Beijing 100089
China

Yan Yu

Shanghai Jiao Tong University (SJTU) - Shanghai Municipality Key Laboratory of Veterinary Biotechnology ( email )

Shanghai 200030, Shanghai 200052
China

Wei Han (Contact Author)

Shanghai Jiao Tong University (SJTU) - Laboratory of Regeneromics ( email )

Shanghai 200030, Shanghai 200052
China

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