Mesothelial cell autoantibodies upregulate transcription factors associated with fibrosis

Abstract

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.

Keywords:

• Amphibole asbestos
• autoimmunity
• pleural fibrosis

Acknowledgements

The authors wish to acknowledge Dr. Kinta Serve, Mars Hill University, for her editorial and intellectual contributions to this work. We further dedicate this work to the memory of Dr. Steven Levin, who developed the LERP and whose insights inspired our continued research.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was supported by grants from the National Institutes of Health: R15 ES021884-01 and INBRE P20 GM103408, and from the CDC/ATSDR TS000099-01 (Libby Epidemiology Research Program, LERP).