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 beta 1 (TGF-beta 1) 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-beta 1 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-beta 1 and alter its organ distribution. Radiolabeled latent TGF-beta 1 was formed by noncovalent association of 125I-TGF-beta 1 with the TGF-beta 1 precursor "pro" region from recombinant sources. TGF-beta 1 in this latent complex had a greatly extended plasma half-life (greater than 100 min) in rats compared with active TGF-beta 1 (2-3 min). Whereas active TGF-beta 1 was rapidly taken up by the liver, kidneys, lungs, and spleen and degraded, TGF-beta 1 in the latent complex was largely confined to the circulation, and was less than 5% degraded after 90 min. The pharmacokinetics of TGF-beta 1 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-beta 1 from an autocrine/paracrine mode of action to a more endocrine mode involving target organs distant from the site of synthesis.
Wakefield
L M
LM
Laboratory of Chemoprevention, National Cancer Institute, Bethesda, Maryland 20892.
Winokur
T S
TS
Hollands
R S
RS
Christopherson
K
K
Levinson
A D
AD
Sporn
M B
MB
D000818:Animals; D001345:Autoradiography; D008657:Metabolic Clearance Rate; D008970:Molecular Weight; D010446:Peptide Fragments / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D012794:Sialic Acids / Q000502:physiology; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics*
D010446:Peptide Fragments; D011498:Protein Precursors; D011994:Recombinant Proteins; D012794:Sialic Acids; D016212:Transforming Growth Factor beta