Transforming Growth Factor-Beta Activation in Irradiated Murine Mammary Gland

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Abstract

The biological activity of TGF-beta, an important modulator of cell proliferation and extracellular matrix formation, is governed by dissociation of mature TGF-beta from an inactive, latent TGF-beta complex in a process that is critical to its role in vivo. So far, it has not been possible to monitor activation in vivo since conventional immunohistochemical detection does not accurately discriminate latent versus active TGF-beta, nor have events associated with activation been defined well enough to serve as in situ markers of this process. We describe here a modified immunodetection method using differential antibody staining that allows the specific detection of active versus latent TGF-beta. Under these conditions, we report that an antibody raised to latency-associated peptide detects latent TGF-beta, and we demonstrate that LC(1-30) antibodies specifically recognize active TGF-beta1 in tumor xenografts overproducing active TGF-beta1, without cross-reactivity in tumors expressing similar levels of latent TGF-beta1. We previously reported that TGF-beta immunoreactivity increases in murine mammary gland after whole-body Cobalt-60-gamma radiation exposure. Using differential antibody staining we now show that radiation exposure specifically generates active TGF-beta1. While latent TGF-beta1 was widely distributed in unirradiated tissue, active TGF-beta1 distribution was restricted. Active TGF-beta1 increased significantly within 1 h of irradiation concomitant with decreased latent TGF-beta immunoreactivity. This rapid shift in immunoreactivity provides the first evidence for activation of TGF-beta in situ. This reciprocal pattern of expression persisted for 3 d and was accompanied by decreased recovery of latent TGF-beta1 from irradiated tissue. Radiation-induced activation of TGF-beta may have profound implications for understanding tissue effects caused by radiation therapy. (J. Clin. Invest. 1994. 93:892-899.) Key words: ionizing radiation. transforming growth factor-beta. mammary gland. immunohistochemistry. extracellular matrix

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