Environmental Health Perspectives 105, Supplement 6, December 1997

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Modulation with Cytokines of Radiation Injury: Suggested Mechanisms of Action

Ruth Neta

Office of International Health Programs, U.S. Department of Energy, Germantown, Maryland

Abstract
Cytokines, hormonelike proteins, produced by stimulated cells and tissues, were found to protect mice against lethal hematopoietic failure caused by ionizing radiation. Radioprotection was achieved by pretreatment with interleukin-1 (IL-1), tumor necrosis factor (TNF), IL-12, or stem cell factor (SCF) at 18 to 24 hr before irradiation. Pretreatment with antibodies to these cytokines rendered the mice more susceptible to radiation lethality, indicating that these cytokines play a role in innate resistance to radiation. In contrast, treatment with tumor growth factor beta (TGF-ß), a cytokine that inhibits cycling of primitive hematopoietic progenitors, sensitized mice to radiation lethality. The schedule of IL-1 administration was critical to its radioprotective effect. Evidence was obtained that this may be based on the induction of additional cytokines by IL-1. The radioprotective effects of cytokines can be based on induction of cycling of primitive progenitor cells (IL-1, SCF), prevention of apoptosis (SCF), and induction of scavenging proteins and enzymes (IL-1, TNF) that reduce oxidative damage. In contrast, radiosensitizing effects may be due to inhibition of progenitor cycling (TGF-ß) or enhanced progenitor cell apoptosis (TGF-ß). Thus, the insights gained from such studies at the whole-animal level promise a better understanding of the membrane and intracellular events associated with radiation damage and repair of such damage. -- Environ Health Perspect 105(Suppl 6):1463-1465 (1997)

Key words: cytokines, radiation, radioprotection, radiation injury, interleukin-1, tumor necrosis factor, stem cell factor, tumor growth factor beta

This paper is based on a presentation at the International Conference on Radiation and Health held 3-7 November 1996 in Beer Sheva, Israel. Abstracts of these papers were previously published in Public Health Reviews 24(3-4):205-431 (1996). Manuscript received at EHP 18 April 1997; accepted 2 July 1997.

Address correspondence to Dr. R. Neta, Office of International Health Programs, U.S. Department of Energy, 19901 Germantown Rd, Germantown, MD 20874. Telephone: (301) 903-1757. Fax: (301) 903-1413. E-mail: ruth.neta@eh.doe.gov

Abbreviations used: cGy, centigray; EPO, erythropoietin; 5-FU, 5-fluorouracil; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte- macrophage colony-stimulating factor; Gy, gray; HU, hydroxyurea; IFN, interferon; IL, interleukin; M-CSF, macrophage colony-stimulating factor; NFkappaB, nuclear factor kappaB; SCF, stem-cell factor; TGF, transforming growth factor; TNF, tumor necrosis factor; TPO, thrombopoietin.

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