Reduced hematopoietic function and enhanced radiosensitivity of transforming growth factor-beta 1 transgenic mice

The cytokine transforming growth factor-beta 1 (TGF-beta 1) has been implic ated in some tissue responses to radiation. Previous studies have demonstra ted that exogenous TGF-beta 1 increased the lethality of radiation in mice, but the effects of endogenous TGF-beta 1 have not been investigated. To th is end, we examined mice that are transgenic for active TGF-beta 1 (Alb/TGF -beta 1), over-expressed via an albumin promoter in the liver with resultan t elevation of circulating levels of this cytokine. Alb/TGF-beta 1 mice sub jected to 8 Gy of total body irradiation at 3 or 5 weeks of age experienced significantly higher mortality than wild type age- and sex-matched control s by 1 to 2 weeks after irradiation. Alb/TGF-beta 1 3 weeks of age also suc cumbed to 2 and 4 Gy of whole-body irradiation, while no mortality was obse rved in wild type mice. Four-week-old Alb/TGF-beta 1 mice exhibited mild an emia and mild uremia. At one week after whole body irradiation with 2 Gy, 4 -week-old Alb/TGF-beta 1 mice had significantly reduced white blood cell co unts, hematocrit, and platelet counts. Histopathologically, irradiated Alb/ TGF-beta 1 mice exhibited decreased bone marrow cellularity and decreased s plenic extramedullary hematopoiesis. These results suggest that chronic ove r-expression of active TGF-beta 1 is associated with increased radiosensiti vity and that this effect may be mediated by increased sensitivity of bone marrow to the suppressive effects of radiation. Since TGF-beta 1 levels can be greatly elevated inpatients with certain tumors, these findings may be significant for radiotherapy. Published 2000 Wiley-Liss, Inc.(dagger).