Contrasting mechanisms of the myeloprotective effects of interleukin-1 against ionizing radiation and cytotoxic 5-fluorouracil.
Pretreatment with a single dose of interleukin-1 (IL-1) counteracts the myelosuppressive effects of radiation. In contrast, multiple doses are required to protect against several cytoablative drugs, suggesting different mechanisms. We examined the possibility that myeloprotection is due to IL-1-induced cycling of primitive progenitor cells. First, we evaluated the effect of the time between administration of IL-1 and 5-fluorouracil (5-FU), which kills cycling cells but spares quiescent early progenitors, on their interaction. Pretreatment with a single dose of IL-1 resulted in the death of mice treated with 5-FU provided IL-1 was given 18 h, but not 4 or 48 h, prior to administration of sublethal doses of 5-FU. Second, evaluation of primitive hematopoietic progenitor cells, 13-day spleen colony-forming units (CFU-S) and CFU with high proliferative potential revealed that treatment with 5-FU 18 h after administration of IL-1 results in reduction of CFU-S by 98% and of CFU with high proliferative potential by 65%, but only a 7 and 10% reduction, respectively, at 48 h. Third, in contrast to protection from death by pretreatment with a single dose of IL-1 at 24 h, two injections of IL-1 at 72 and 24 h before irradiation abrogated such protection. Similarly, the toxicity of 5-FU to progenitor cells was reduced when two injections of IL-1 were administered 48 h apart. This correlates with the time of up-regulation in the bone marrow cells of TGF-beta. These findings suggest that, depending on the schedule of treatment, administration of IL-1 may result in cycling of primitive progenitors, to protect against radiation, and may cause inhibition of cycling to protect against chemotherapeutic drugs.