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Latent transforming growth factor beta1 activation in situ: quantitative and functional evidence after low-dose gamma-irradiationThe biological activity of transforming growth factor beta1 (TGF-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 activation in situ.
Document ID
Document Type
Reprint (Version printed in journal)
Ehrhart, E. J.
(Colorado State University Ft. Collins 80523, United States)
Segarini, P.
Tsang, M. L.
Carroll, A. G.
Barcellos-Hoff, M. H.
Chatterjee, A.
Date Acquired
August 22, 2013
Publication Date
October 1, 1997
Publication Information
Publication: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume: 11
Issue: 12
ISSN: 0892-6638
Subject Category
Life Sciences (General)
Distribution Limits
NASA Discipline Radiation Health
Non-NASA Center
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