We are investigating cytokines with beneficial or detrimental effects on hematopoietic recovery from radiation damage to identify the molecular basis of radioprotection and radiosensitization by cytokines. We are comparing the effects of protective cytokines such as IL-1 and Stem Cell Factor (SCF) with suppressive TGFbeta on the expression of cell cycle genes. We have obtained the following experimental results. Irradiation induces high levels of p21 mRNA expression by murine bone marrow cells (BMC) both in vivo and in vitro. Both IL-1 and SCF stimulated low levels of p21 mRNA in BMC of untreated mice. They synergistically enhanced p21 mRNA levels in BMC of irradiated mice and concomitantly prolonged the survival of lethally irradiated mice. IL-1 and SCF also enhanced p21 mRNA expression induced by camptothecin in a B cell line derived from homozygous p53 deficient mice suggesting that the cytokines effect p21 independent of p53. TGFbeta which is a radiosensitizer also transiently enhances p21 mRNA expression by irradiated BMC, but to a lesser extent than IL-1 or SCF. However, unlike IL-1 and irradiation which decreased the level of cyclin A, TGFbeta did not suppress the cyclin A mRNA. Furthermore, TGFbeta, unlike IL-1 induces another inhibitor of cyclin cdk complexes, namely p27. The effect of these cytokines with opposing hematopoietic effects on other cell cycle, repair and apoptosis genes is to be investigated. The ultimate goal of these studies is to learn how these cytokines restore hematopoiesis, and influence the cell cycle, cell survival and DNA repair of bone marrow cells following irradiation.
