IL-12 protects bone marrow from and sensitizes intestinal tract to ionizing radiation.
IL-12, a potent stimulator of hemopoietic progenitor cells, was evaluated as a potential protector against 60Co-gamma radiation-induced lethal hemopoietic syndrome in mice. Administration of IL-12 before lethal irradiation of genetically distinct strains of mice, B6D2F1 and C3H/HeJ, protected a significant fraction of both strains of mice from death. Radioprotection was associated with a fivefold increase in the number of bone marrow cells at 6 days after irradiation. Even at supralethal doses of radiation (1200 cGy), the number of c-kit+ bone marrow cells 3 days after irradiation was twofold greater in IL-12-treated mice than in saline-treated mice. However, mice that received IL-12 and 1200 cGy (B6D2F1) or 900 cGy (C3H/HeJ) died of the gastrointestinal syndrome, as was evident by gross necroscopy and histologic evaluation, within 4 to 6 days after irradiation. Induction of the gastrointestinal syndrome in mice not treated with IL-12 required radiation doses of 1500 cGy or greater in both strains. Thus, at doses of radiation at which IL-12 still protects c-kit+ hemopoietic cells, it sensitizes the intestinal tract to damage. Radioprotection with IL-12 was abrogated by anti-IL-1R or anti-stem cell factor Ab. Anti-IFN-gamma Ab did not affect IL-12-induced hemopoietic radioprotection, but abrogated sensitization of the intestinal tract by IL-12. The sensitizing effect of IL-12 may be related to its ability to prime mice to subsequent inflammatory challenge, as demonstrated by an almost 100-fold increase in circulating TNF and IL-6 levels in normal B6D2F1 mice challenged with IL-12 and LPS. This priming effect of IL-12 also was abrogated by anti-IFN-gamma Ab.
Neta
R
R
Department of Experimental Hematology, Armed Forces Radiobiology Research Institute, Bethesda, MD 20889.
Stiefel
S M
SM
Finkelman
F
F
Herrmann
S
S
Ali
N
N
D000818:Animals; D001853:Bone Marrow / Q000528:radiation effects*; D005260:Female; D016298:Hematopoietic Cell Growth Factors / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000528:radiation effects*; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D011833:Radiation Injuries, Experimental / Q000276:immunology; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D017472:Receptors, Interleukin-1 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016298:Hematopoietic Cell Growth Factors; D015850:Interleukin-6; D011837:Radiation-Protective Agents; D011838:Radiation-Sensitizing Agents; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma