IL-1Ra Protects Hematopoietic Cells from Chemotoxicity Through P53-induced Quiescence

Overview

Journal FASEB J

Specialties Biology
Physiology

Date 2019 Aug 3

PMID 31373847

Citations 4

Authors

Hao Ye

Lan Qian

Shunying Zhu

Shaorong Deng

Xia Wang

Jiang Zhu

Gerald L Chan

Yan Yu

Wei Han

Affiliations

Soon will be listed here.

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, pretreatment of recombinant human IL-1 receptor antagonist (rhIL-1Ra) protected both types of vulnerable tissues from chemotherapeutics. Here, we showed that rhIL-1Ra treatment up-regulated the protein levels of phosphorylated p38, p53, and p21 and induced transient hematopoietic stem/progenitor cell (HS/PC) quiescence. Knockout of IL-1 receptor I (), , or alleles and pharmacological inactivation of p38 mapped the rhIL-1Ra pathway in the induction of HS/PC quiescence. Therefore, rhIL-1Ra administration before but not after chemotherapy alleviated 5-fluorouracil-induced neutropenia. In addition, and cell proliferation assays revealed that the rhIL-1Ra treatment did not affect cancer cell proliferation or chemosensitivity. Lastly, we propose an IL-1/IL-1Ra pathway (IL-1RI → p38 → p53 → p21), which regulates HS/PC quiescence. The rhIL-1Ra may provide a new route for p53-based cyclotherapy, which spares normal cells but kills cancer cells during chemotherapy.-Ye, H., Qian, L., Zhu, S., Deng, S., Wang, X., Zhu, J., Chan, G. L., Yu, Y., Han, W. IL-1Ra protects hematopoietic cells from chemotoxicity through p53-induced quiescence.

Citing Articles

Identification of the natural chalcone glycoside hydroxysafflor yellow A as a suppressor of P53 overactivation-associated hematopoietic defects.

Chen J, Ren C, Yao C, Baruscotti M, Wang Y, Zhao L MedComm (2020). 2023; 4(5):e352.

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Selective protection of normal cells from chemotherapy, while killing drug-resistant cancer cells.

Blagosklonny M Oncotarget. 2023; 14:193-206.

PMID: 36913303 PMC: 10010629. DOI: 10.18632/oncotarget.28382.

Molecular regulation of hematopoietic stem cell quiescence.

Chen Z, Guo Q, Song G, Hou Y Cell Mol Life Sci. 2022; 79(4):218.

PMID: 35357574 PMC: 11072845. DOI: 10.1007/s00018-022-04200-w.

Secretory galectin-3 induced by glucocorticoid stress triggers stemness exhaustion of hepatic progenitor cells.

Yang F, Zhang F, Ji X, Jiang X, Xue M, Yu H J Biol Chem. 2020; 295(49):16852-16862.

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References

Gallagher R, Collins S, Trujillo J, McCredie K, AHearn M, Tsai S . Characterization of the continuous, differentiating myeloid cell line (HL-60) from a patient with acute promyelocytic leukemia. Blood. 1979; 54(3):713-33. View

Gartel A, Tyner A . Transcriptional regulation of the p21((WAF1/CIP1)) gene. Exp Cell Res. 1999; 246(2):280-9. DOI: 10.1006/excr.1998.4319. View

Karimian A, Ahmadi Y, Yousefi B . Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair (Amst). 2016; 42:63-71. DOI: 10.1016/j.dnarep.2016.04.008. View

Batchelor E, Loewer A, Lahav G . The ups and downs of p53: understanding protein dynamics in single cells. Nat Rev Cancer. 2009; 9(5):371-7. PMC: 2892289. DOI: 10.1038/nrc2604. View

Blagosklonny M, Pardee A . The restriction point of the cell cycle. Cell Cycle. 2002; 1(2):103-10. View

Wilson A, Laurenti E, Oser G, van der Wath R, Blanco-Bose W, Jaworski M . Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell. 2008; 135(6):1118-29. DOI: 10.1016/j.cell.2008.10.048. View

Hui L, Bakiri L, Mairhorfer A, Schweifer N, Haslinger C, Kenner L . p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nat Genet. 2007; 39(6):741-9. DOI: 10.1038/ng2033. View

Khemissa F, Mineur L, Amsellem C, Assenat E, Ramdani M, Bachmann P . A phase III study evaluating oral glutamine and transforming growth factor-beta 2 on chemotherapy-induced toxicity in patients with digestive neoplasm. Dig Liver Dis. 2016; 48(3):327-32. DOI: 10.1016/j.dld.2015.11.025. View

Zhang J, Xiang D, Zhu S, Mao W, Lu H, Wu M . Interleukin 1 receptor antagonist inhibits normal hematopoiesis and reduces lethality and bone marrow toxicity of 5-fluouracil in mouse. Biomed Pharmacother. 2008; 63(7):501-8. DOI: 10.1016/j.biopha.2008.09.014. View

10.

Dinarello C . Biologic basis for interleukin-1 in disease. Blood. 1996; 87(6):2095-147. View

11.

Carey A, Edwards 5th D, Eide C, Newell L, Traer E, Medeiros B . Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia. Cell Rep. 2017; 18(13):3204-3218. PMC: 5437102. DOI: 10.1016/j.celrep.2017.03.018. View

12.

Johnson A, Skotheim J . Start and the restriction point. Curr Opin Cell Biol. 2013; 25(6):717-23. PMC: 3836907. DOI: 10.1016/j.ceb.2013.07.010. View

13.

Yu H, Wu M, Wen B, Sun N, Xiang D, Zhang J . Antagonist effect of Interleukin 1 receptor on normal thymopoiesis and thymus toxicity of 5-azacytidine in mouse. Am J Transl Res. 2016; 8(2):1237-45. PMC: 4846967. View

14.

Liu Y, Elf S, Miyata Y, Sashida G, Liu Y, Huang G . p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell. 2009; 4(1):37-48. PMC: 2839936. DOI: 10.1016/j.stem.2008.11.006. View

15.

Olson T, Caselli A, Otsuru S, Hofmann T, Williams R, Paolucci P . Megakaryocytes promote murine osteoblastic HSC niche expansion and stem cell engraftment after radioablative conditioning. Blood. 2013; 121(26):5238-49. PMC: 3695366. DOI: 10.1182/blood-2012-10-463414. View

16.

Velardi E, Tsai J, Radtke S, Cooper K, Argyropoulos K, Jae-Hung S . Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury. Nat Med. 2018; 24(2):239-246. PMC: 5803436. DOI: 10.1038/nm.4470. View

17.

Jiang L, Zhang N, Ding F, Li X, Chen L, Zhang H . RA-inducible gene-I induction augments STAT1 activation to inhibit leukemia cell proliferation. Proc Natl Acad Sci U S A. 2011; 108(5):1897-902. PMC: 3033283. DOI: 10.1073/pnas.1019059108. View

18.

Blagosklonny M, Pardee A . Exploiting cancer cell cycling for selective protection of normal cells. Cancer Res. 2001; 61(11):4301-5. View

19.

Zhang Y, Gao J, Wang X, Deng S, Ye H, Guan W . CXCL4 mediates tumor regrowth after chemotherapy by suppression of antitumor immunity. Cancer Biol Ther. 2015; 16(12):1775-83. PMC: 4847813. DOI: 10.1080/15384047.2015.1095404. View

20.

Rumman M, Dhawan J, Kassem M . Concise Review: Quiescence in Adult Stem Cells: Biological Significance and Relevance to Tissue Regeneration. Stem Cells. 2015; 33(10):2903-12. DOI: 10.1002/stem.2056. View