Gene Expression of Hematoregulatory Cytokines is Elevated Endogenously After Sublethal Gamma Irradiation and is Differentially Enhanced by Therapeutic Administration of Biologic Response Modifiers
ARMED FORCES RADIOBIOLOGY RESEARCH INST BETHESDA MD
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Prompt, cytokine-mediated restoration of hematopoiesis is a prerequisite for survival after irradiation. Therapy with biologic response modifiers BRMs, such as LPS, 3D monophosphoryl lipid A MPL, and synthetic trehalose dicorynomycolate S-TDCM presumably accelerate hematopoietic recovery after irradiation by enhancing expression of cytokine. However, the kinetics of the cytokine gene response to BRMs andor irradiation are poorly defined. One hour after sublethal 7.0 Gy Cobalt gamma irradiation, B6D2F1J female mice received a single i.p. injection of LPS, MPL, S-TDCM, an extract from Serratia marcescens Sm-BRM, or Tween 80 in saline TS. Five hours later, a quantitative reverse transcription-PCR assay demonstrate marked splenic gene expression for IL-1 Beta, IL-6, and granulocyte-CSFG CSF. Enhanced gene expression for TNF-Alpha, Macrophage-CSF M CSF, and stem cell factor SCF was not detected. Injection of any BRM further enhanced cytokine gene expression and plasma levels of CSF activity within 24 h after irradiation and hastened bone marrow recovery. Mice injected with S-TDCM or Sm-BRM sustained expression of the IL-6 gene for at least 24 h after irradiation. Sm-BRM-treated mice exhibited greater expression for IL-1 Beta, IL-3, TNF-alpha, and G-CSF at day 1 than any other BRM. When challenged with 2 LD5030 of Klesiella pneumoniae 4 days after irradiation, 100 of SM-BRm-treated mice and 70 of S-TDCM-treated mice survived, whereas less than 30 of mice treated with LPS, MPL, or TS survived.
- Medicine and Medical Research