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 radioprotection, 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 that 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 radioprotection. SCF, unlike IL-1, does not induce hemopoietic CSFs and IL-6 or gene expression of a scavenging mitochondrial enzyme manganese superoxide dismutase in the bone marrow, suggesting that SCF and IL-1 radioprotect by distinct pathways. The mRNA expression for c-kit (by Northern blot 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 increased sixfold in IL-1-treated mice, almost 20-fold in SCF-treated mice, and 40-fold in mice treated with the combination of the two cytokines. Thus, endogenous production of both IL-1 and SCF is required for resistance to lethal irradiation and the synergistic radioprotective effect of the two cytokines may, in part, depend on IL-1 and SCF-induced increases in numbers of c-kit(+) hemopoietic stem and progenitors cells that survive lethal irradiation.