SYNERGY OF IL-1 AND STEM-CELL FACTOR IN RADIOPROTECTION OF MICE IS ASSOCIATED WITH IL-1 UP-REGULATION OF MESSENGER-RNA AND PROTEIN EXPRESSION FOR C-KIT ON BONE-MARROW CELLS

Administration of IL-1 and stem cell factor (SCF) to mice 18 h before lethal Co-60 whole-body irradiation resulted in synergistic radioprote ction, as evidenced by increased numbers of mice surviving 1,200 to 1, 300 cGy doses of radiation and the recovery of increased numbers of c- kit(+) bone marrow cells at 1 and 4 days after the lethal dose of 950 cGy. Anti-SCF Ab inhibited IL-1-induced radioprotection, indicating th at endogenous production of SCF is necessary for radioprotection by IL -1. Conversely, radioprotection induced by SCF was reduced by anti-IL- 1R Ab, indicating that endogenous IL-1 contributes to SCF radioprotect ion. SCF, unlike IL-1, does not induce hemopoietic CSFs and IL-6 or ge ne expression of a scavenging mitochondrial enzyme manganese superoxid e dismutase in the bone marrow, suggesting that SCF and IL-1 radioprot ect by distinct pathways. The mRNA expression for c-kit (by Northern b lot analysis) and I-125-SCF binding on bone marrow cells was elevated within 2 and 4 h of IL-1 administration respectively. Four days after LD 100/30 radiation the recovery of c-kit(+) bone marrow cells was inc reased sixfold in IL-1-treated mice, almost 20-fold in SCF-treated mic e, and 40-fold in mice treated with the combination of the two cytokin es. Thus, endogenous production of both IL-1 and SCF is required for r esistance to lethal irradiation and the synergistic radioprotective ef fect of the two cytokines may, in part, depend on IL-1 and SCF-induced increases in numbers of c-kit(+) hemopoietic stem and progenitors cel ls that survive lethal irradiation.