Latent transforming growth factor beta 1 activation in situ: quantitative and functional evidence after low-dose gamma-irradiation

被引:195
作者
Ehrhart, EJ
Segarini, P
Tsang, MLS
Carroll, AG
BarcellosHoff, MH
机构
[1] UNIV CALIF BERKELEY, LAWRENCE BERKELEY LAB, DIV LIFE SCI, BERKELEY, CA 94720 USA
[2] COLORADO STATE UNIV, FT COLLINS, CO 80523 USA
[3] CELTRIX PHARMACEUT INC, SANTA CLARA, CA 95050 USA
[4] R&D SYST INC, MINNEAPOLIS, MN 55413 USA
关键词
ionizing radiation; reactive oxygen species; mammary gland; extracellular matrix; collagen; gene expression;
D O I
10.1096/fasebj.11.12.9337152
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The biological activity of transforming growth factor beta 1 (TCF-beta) is controlled by its secretion as a latent complex in which it is noncovalently associated with latency-associated peptide (LAP). Activation is the extracellular process in which TGF-beta is released from LAP, and is considered to be a primary regulatory control, We recently reported rapid and persistent changes in TGF-beta immunoreactivity in conjunction with extracellular matrix remodeling in gamma-irradiated mouse mammary gland, Our hypothesis is that these specific changes in immunoreactivity are indicative of latent TGF-beta activation, In the present study, we determined the radiation dose response and tested whether a functional relationship exists between radiation-induced TGF-beta and collagen type III remodeling, After radiation exposures as low as 0.1 Gy, we detected increased TGF-beta immunoreactivity in the mammary epithelium concomitant with decreased LAP immunostaining, which are events consistent with activation, Quantitative image analysis demonstrated a significant (P=0.0005) response at 0.1 Gy without an apparent threshold and a linear dose response to 5 Gy, However, in the adipose stroma, loss of LAP demonstrated a qualitative threshold at 0.5 Gy, Loss of LAP paralleled induction of collagen III immunoreactivity in this tissue compartment, We tested whether TGF-beta mediates collagen III expression by treating animals with TGF-beta panspecific monoclonal antibody, 1D11.16, administered i.p. shortly before irradiation, Radiation-induced collagen III staining in the adipose stroma was blocked in an antibody dose-dependent manner, which persisted through 7 days postirradiation, RNase protection assay revealed that radiation-induced elevation of total gland collagen III mRNA was also blocked by neutralizing antibody treatment, These data provide functional confirmation of the hypothesis that radiation exposure leads to latent TGF-beta activation, support our interpretation of the reciprocal shift in immunoreactivity as evidence of activation, and implicate TGF-beta as a mediator of tissue response to ionizing radiation, The sensitivity of activation to low radiation doses points to a potential role for TGF-beta in orchestrating tissue response to oxidative stress, As such, radiation may be useful as a probe to delineate the consequences of latent TGF-beta 1 activation in situ.
引用
收藏
页码:991 / 1002
页数:12
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