GENE-EXPRESSION OF HEMATOREGULATORY CYTOKINES IS ELEVATED ENDOGENOUSLY AFTER SUBLETHAL GAMMA-IRRADIATION AND IS DIFFERENTIALLY ENHANCED BY THERAPEUTIC ADMINISTRATION OF BIOLOGIC RESPONSE MODIFIERS

Prompt, cytokine-mediated restoration of hematopoiesis is a prerequisi te for survival after irradiation. Therapy with biologic response modi fiers (BRMs), such as LPS, 3D monophosphoryl lipid A (MPL), and synthe tic trehalose dicerynomycolate (S-TDCM) presumably accelerates hematop oietic recovery after irradiation by enhancing expression of cytokines . However, the kinetics of the cytokine gene response to BRMs and/or i rradiation are poorly defined. One hour after sublethal (7.0 Gy) (60)C obalt gamma irradiation, B6D2F1/J female mice received a single i.p. i njection of LPS, MPL, S-TDCM, an extract from Serratia marcescens (Sm- BRM), or Tween 80 in saline (TS). Five hours later, a quantitative rev erse transcription-PCR assay demonstrated marked splenic gene expressi on for IL-1 beta, IL-3, IL-6, and granulocyte-CSF (G-CSF). Enhanced ge ne expression for TNF-alpha, macrophage-CSF (M-CSF), and stem cell fac tor (SCF) was not detected. Injection of any BRM further enhanced cyto kine gene expression and plasma levels of CSF activity within 24 h aft er 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 gene expres sion for IL-1 beta, IL-3, TNF-alpha, and G-CSF at day 1 than any other BRM. When challenged with 2 LD(50/30) of Klebsiella pneumoniae 4 days after irradiation, 100% of Sm-BRM-treated mice and 70% of S-TDCM-trea ted mice survived, whereas less than or equal to 30% of mice treated w ith LPS, MPL, or TS survived. Thus, sublethal irradiation induces tran sient, splenic cytokine gene expression that can be differentially amp lified and prolonged by BRMs. BRMs that sustained and/or enhanced irra diation-induced expression of specific cytokine genes improved surviva l after experimental infection.