MODULATION WITH CYTOKINES OF RADIATION-INJURY - SUGGESTED MECHANISMS OF ACTION

Cytokines, hormonelike proteins, produced by stimulated cells and tiss ues, were found to protect mice against lethal hematopoietic failure c aused by ionizing radiation. Radioprotection was achieved by pretreatm ent 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 i n innate resistance to radiation. In contrast, treatment with tumor gr owth factor beta (TGF-beta), a cytokine that inhibits cycling of primi tive hematopoietic progenitors, sensitized mice to radiation lethality . The schedule of IL-1 administration was critical to its radioprotect ive effect. Evidence was obtained that this may be based on the induct ion of additional cytokines by IL-1. The radioprotective effects of cy tokines can be based on induction of cycling of primitive progenitor c ells (IL-1, SCF), prevention of apoptosis (SCF), and induction of scav enging proteins and enzymes (IL-1, TNF) that reduce oxidative damage. In contrast, radiosensitizing effects may be due to inhibition of prog enitor cycling (TGF-beta) or enhanced progenitor cell apoptosis (TGF-b eta). 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.