Asbestos-derived reactive oxygen species activate TGF-beta1.
Transforming growth factor-beta1 (TGF-beta1) is a potent peptide that inhibits epithelial and mesenchymal cell proliferation and stimulates the synthesis of extracellular matrix components. This cytokine is produced in a biologically latent complex bound to a latent-associated peptide (LAP), and it is the disassociation of this complex that regulates TGF-beta activity. A number of mechanisms have been shown to activate TGF-beta1. We show here that reactive oxygen species (ROS), generated by the iron in chrysotile or crocidolite asbestos, mediate the biological activity of TGF-beta1. Recombinant human latent TGF-beta1 was activated in a cell free system in the presence of asbestos and ascorbic acid. Latent TGF-beta1 was overexpressed in both A549 and mink lung epithelial cell lines through an adenovirus vector containing the full-length construct for porcine TGF-beta1. This latent TGF-beta1 was activated in a concentration-dependant fashion by introducing asbestos into the cell cultures. This activation was reduced significantly through the use of superoxide dismutase, catalase or deferoxamine. Amino-acid constituents of the LAP were oxidized as demonstrated by the appearance of carbonyls detected by Western analysis. The oxidized LAP could no longer form a complex with TGF-beta1. Our data support the postulate that ROS derived from asbestos provide a mechanism for activating TGF-beta1 in the alveolar environment by oxidizing amino acids in LAP.
Pociask
Derek A
DA
Lung Biology Program, Department of Pathology, Tulane University Health Science Center, New Orleans, LA, USA.
Sime
Patricia J
PJ
Brody
Arnold R
AR
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001194:Asbestos / Q000633:toxicity*; D017638:Asbestos, Crocidolite / Q000633:toxicity; D017632:Asbestos, Serpentine / Q000633:toxicity; D001205:Ascorbic Acid / Q000494:pharmacology; D002460:Cell Line; D002474:Cell-Free System; D006801:Humans; D007501:Iron / Q000378:metabolism; D008907:Mink; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D000975:Antioxidants; D017632:Asbestos, Serpentine; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017638:Asbestos, Crocidolite; D001194:Asbestos; D007501:Iron; D001205:Ascorbic Acid