RECOMBINANT LATENT TRANSFORMING GROWTH FACTOR-BETA-1 HAS A LONGER PLASMA HALF-LIFE IN RATS THAN ACTIVE TRANSFORMING GROWTH FACTOR-BETA-1, AND A DIFFERENT TISSUE DISTRIBUTION

Transforming growth factor β1 (TGF-β1) is a key regulator of cell growth and differentiation. Under normal physiological conditions, it is made as a biologically latent complex whose significance is unknown. Previous work has indicated that active TGF-β1 has a very short plasma half-life in rats (Coffey, R.J., L.J. Kost, R.M. Lyons, H.L. Moses, and N.F. La-Russo. 1987. J. Clin. Invest. 80:750-757). We have investigated the possibility that latent complex formation may extend the plasma half-life of TGF-β1 and alter its organ distribution. Radiolabeled latent TGF-β1 was formed by noncovalent association of 125I-TGFβ1 precursor 'pro' region from recombinant sources. TGF-β1 in this latent complex had a greatly extended plasma half-life (>100 min) in rats compared with active TGF-β1 (2-3 min). Whereas active TGF-β1 was rapidly taken up by the liver, kidneys, lungs, and spleen and degraded, TGF-β1 in the latent complex was largely confined to the circulation, and was <5% degraded after 90 min. The pharmacokinetics of TGF-β1 in the latent complex were shown to be critically dependent on the degree of sialylation of the complex. The results suggest that formation of latent complexes may switch endogenous TGF-β1 from an autocrine/paracrine mode of action to a more endocrine mode involving target organs distant from the site of synthesis.