IL-1Ra Protects Hematopoietic Stem Cells from Chemotoxicity Through Quiescence Induction Via p53
29 Pages Posted: 22 Jan 2019 Sneak Peek Status: Under ReviewMore...
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
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