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 th e myelosuppressive effects of radiation. In contrast, multiple doses a re 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 d ose of IL-1 resulted in the death of mice treated with 5-FU provided I L-1 was given 18 h, but not 4 or 48 h, prior to administration of subl ethal doses of 5-FU. Second, evaluation of primitive hematopoietic pro genitor cells, 13-day spleen colony-forming units (CFU-S) and CFU with high proliferative potential revealed that treatment with 5-FU 18 h a fter 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 fro m death by pretreatment with a single dose of IL-1 at 24 h, two inject ions of IL-1 at 72 and 24 h before irradiation abrogated such protecti on. Similarly, the toxicity of 5-FU to progenitor cells was reduced wh en two injections of IL-1 were administered 48 h apart. This correlate s 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. (C) 1996 by Radiation Research Society