Thrombospondin-1 is a major activator of TGF-beta1 in vivo.
The activity of TGF-beta1 is regulated primarily extracellularly where the secreted latent form must be modified to expose the active molecule. Here we show that thrombospondin-1 is responsible for a significant proportion of the activation of TGF-beta1 in vivo. Histological abnormalities in young TGF-beta1 null and thrombospondin-1 null mice were strikingly similar in nine organ systems. Lung and pancreas pathologies similar to those observed in TGF-beta1 null animals could be induced in wild-type pups by systemic treatment with a peptide that blocked the activation of TGF-beta1 by thrombospondin-1. Although these organs produced little active TGF-beta1 in thrombospondin null mice, when pups were treated with a peptide derived from thrombospondin-1 that could activate TGF-beta1, active cytokine was detected in situ, and the lung and pancreatic abnormalities reverted toward wild type.
Crawford
S E
SE
Robert H. Lurie Cancer Center, Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Stellmach
V
V
Murphy-Ullrich
J E
JE
Ribeiro
S M
SM
Lawler
J
J
Hynes
R O
RO
Boivin
G P
GP
Bouck
N
N
D000818:Animals; D018920:Coculture Techniques; D004847:Epithelial Cells; D005347:Fibroblasts; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009842:Oligopeptides / Q000494:pharmacology; D010179:Pancreas / Q000473:pathology; D010446:Peptide Fragments; D011498:Protein Precursors; D011506:Proteins / Q000494:pharmacology; D012867:Skin / Q000166:cytology; D019700:Thrombospondin 1 / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D009842:Oligopeptides; D010446:Peptide Fragments; D011498:Protein Precursors; D011506:Proteins; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1