Reduced hematopoietic function and enhanced radiosensitivity of transforming growth factor-beta1 transgenic mice.
The cytokine transforming growth factor-beta1 (TGF-beta1) has been implicated in some tissue responses to radiation. Previous studies have demonstrated that exogenous TGF-beta1 increased the lethality of radiation in mice, but the effects of endogenous TGF-beta1 have not been investigated. To this end, we examined mice that are transgenic for active TGF-beta1 (Alb/TGF-beta1), over-expressed via an albumin promoter in the liver with resultant elevation of circulating levels of this cytokine. Alb/TGF-beta1 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-beta1 3 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-beta1 mice exhibited mild anemia and mild uremia. At one week after whole body irradiation with 2 Gy, 4-week-old Alb/TGF-beta1 mice had significantly reduced white blood cell counts, hematocrit, and platelet counts. Histopathologically, irradiated Alb/TGF-beta1 mice exhibited decreased bone marrow cellularity and decreased splenic extramedullary hematopoiesis. These results suggest that chronic over-expression of active TGF-beta1 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-beta1 levels can be greatly elevated in patients with certain tumors, these findings may be significant for radiotherapy. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 13-21 (2000). Published 2000 Wiley-Liss, Inc.
Vodovotz
Y
Y
Radiation Biology Branch, National Cancer Institute, Bethesda, Maryland, USA.
Lucia
M S
MS
DeLucca
A M
AM
Mitchell
J B
JB
Kopp
J B
JB
D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D001806:Blood Urea Nitrogen; D006410:Hematopoiesis / Q000502:physiology*; D007928:Lethal Dose 50; D007958:Leukocyte Count / Q000528:radiation effects; D008099:Liver / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000473:pathology; D011836:Radiation Tolerance / Q000502:physiology*; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014916:Whole-Body Irradiation
D016212:Transforming Growth Factor beta