Synergy of IL-1 and stem cell factor in radioprotection of mice is associated with IL-1 up-regulation of mRNA 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 60Co 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 125I-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.
Neta
R
R
Department of Experimental Hematology, Armed Forces Radiobiology Research Institute, Bethesda, MD 20889.
Oppenheim
J J
JJ
Wang
J M
JM
Snapper
C M
CM
Moorman
M A
MA
Dubois
C M
CM
D000315:Adrenalectomy; D000818:Animals; D004307:Dose-Response Relationship, Radiation; D004357:Drug Synergism; D005260:Female; D005720:Gamma Rays; D015870:Gene Expression / Q000187:drug effects; D016298:Hematopoietic Cell Growth Factors / Q000008:administration & dosage*; D007375:Interleukin-1 / Q000008:administration & dosage*; D015850:Interleukin-6 / Q000502:physiology; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit; D012333:RNA, Messenger / Q000235:genetics; D011837:Radiation-Protective Agents; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics*; D019089:Stem Cell Factor; D013482:Superoxide Dismutase / Q000235:genetics
D016298:Hematopoietic Cell Growth Factors; D007375:Interleukin-1; D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011837:Radiation-Protective Agents; D016184:Receptors, Colony-Stimulating Factor; D019089:Stem Cell Factor; D013482:Superoxide Dismutase; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases