Mesothelial cell autoantibodies upregulate transcription factors associated with fibrosis.
Amphibole asbestos exposure is associated with the production of mesothelial cell autoantibodies (MCAA). These MCAA have been linked with pleural fibrotic disease in the asbestos exposed community of Libby, Montana, and induce collagen deposition by cultured mesothelial cells. However, the exact intracellular mechanism by which these autoantibodies cause an increase in collagen deposition remains unknown. This study sought to gain insight into the transcription factors involved in the collagen production after human mesothelial cells are exposed to MCAA. In this study, transcription factor activation profiles were generated from human mesothelial cells (Met5A) treated with serum from Libby subjects, and were compared to cells treated with serum cleared of IgG, and therefore containing no MCAA. Analysis of those profiles indicated C/EBP-beta and hypoxia inducible factor 1 alpha (HIF-1α) are significantly increased in the nucleus, indicating activation, due to MCAA exposure compared to controls. Inhibition of either of these transcription factors significantly reduced collagen 1 deposition by these cells following exposure to MCAA. These data suggest autoantibodies are directly involved in type I collagen deposition and may elucidate potential therapeutic targets for autoantibody mediated fibrosis.
a Department of Biological Sciences , Idaho State University , Pocatello , ID , USA.
John
J
Gilmer
a Department of Biological Sciences , Idaho State University , Pocatello , ID , USA.
Tanner
T
Harding
a Department of Biological Sciences , Idaho State University , Pocatello , ID , USA.
Linda
L
Woods
b Center for Asbestos Related Diseases , Libby , MT , USA.
Brad
B
Black
c Department of Thoracic Surgery , Icahn School of Medicine at Mt Sinai , New York , NY , USA.
Raja
R
Flores
d Department of Microbiology and Immunology , Montana State University , Bozeman , MT , USA.
Jean
J
Pfau
D017636:Asbestos, Amphibole; D001323:Autoantibodies / Q000276:immunology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000096:biosynthesis*; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology*; D005355:Fibrosis / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D016273:Occupational Exposure; D044967:Serum; D015854:Up-Regulation
D017636:Asbestos, Amphibole; D001323:Autoantibodies; D022782:CCAAT-Enhancer-Binding Protein-beta; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D003094:Collagen
Amphibole asbestos; autoimmunity; pleural fibrosis