Reduced hematopoietic function and enhanced radiosensitivity of transforming growth factor-β1 transgenic mice

The cytokine transforming growth factor-β1 (TGF-β1) has been implicated in some tissue responses to radiation. Previous studies have demonstrated that exogenous TGF-β1 increased the lethality of radiation in mice, but the effects of endogenous TGFβ1 have not been investigated. To this end, we examined mice that are transgenic for active TGF-β1 (Alb/TGF- β1), over-expressed via an albumin promoter in the liver with resultant elevation of circulating levels of this cytokine. Alb/TGF-β1 mice subjected 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 controls by 1 to 2 weeks after irradiation. Alb/TGF-β13 weeks of age also succumbed to 2 and 4 Gy of whole-body irradiation, while no mortality was observed in wild type mice. Four-week-old Alb/TGF-β1 mice exhibited mild anemia and mild uremia. At one week after whole body irradiation with 2 Gy, 4-week-old Alb/TGF-β1 mice had significantly reduced white blood cell counts, hematocrit, and platelet counts. Histopathologically, irradiated Alb/TGF-β1 mice exhibited decreased bone marrow cellularity and decreased splenic extramedullary hematopoiesis. These results suggest that chronic over- expression of active TGF-β1 is associated with increased radiosensitivity and that this effect may be mediated by increased sensitivity of bone marrow to the suppressive effects of radiation. Since TGF-β1 levels can be greatly elevated in patients with certain tumors, these findings may be significant for radiotherapy.