Mesothelial cell autoantibodies upregulate transcription factors associated with fibrosis

Abstract

Amphibole asbestos exposure is associated with 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.

Relevância do perfil morfológico, molecular e imunomatricial como sinalizadores de alvos terapêuticos no mesotelioma maligno

“…Além disso, relatórios anteriores sugerem que o amianto pode prejudicar gradualmente a imunidade antitumoral 164 . Kumagai-Takei e colaboradores 165 demonstraram que os pacientes com MM apresentam comprometimento da citotoxicidade induzida pela estimulação dos linfócitos CD8 do sangue periférico, possivelmente relacionado à exposição ao amianto. Além disso, a exposição ao amianto está associada à produção de auto-anticorpos para células malignas e induz a deposição de colágeno por células malignas cultivadas 166 .…”