CURRENT CONCEPTS OF CAUSATION OF MESOTHELIOMA BY AMPHIBOLE ASBESTOS AND ERIONITE

Both asbestos and erionite fibers are associated with causation of malignant mesothelioma (MM), a unique and aggressive disease of the pleural or peritoneal cavity. Among various asbestos fibers crocidolite is considered to be the most oncogenic type of asbestos. The long and thin fibers are thought to be more dangerous because they have longer biopersistance in the pleura and they can penetrate the lung and cause repeated damage, tissue repair and local inflammation. Erionite is another potent fiber that induces MM. Erionite has been detected in the lungs of villagers in several towns in Cappadocia, Turkey, where 50% or more of deaths are caused by MM. Mesothelial cells lining the pleural or peritoneal cavity are target cells of fiber-associated MM. Acute and chronic inflammation has been attributed to the development of asbestos-induced diseases. Here we describe that the inflammasome, a component of the inflammation cascade, is activated in mesothelial cells and contributes to MM. We show using human mesothelial cells (LP9) that both asbestos and erionite can cause priming of the Nod-like receptor-family protein3 inflammasome (NLRP3), activation of caspase-1 and IL-1β and high mobility group box1 (HMGB1) protein release. Increased steady-state mRNA levels of NLRP3, IL-1β, IL-6 and IL-8, and release of IL-1β, IL-6, IL-8 and VEGF (essential chemokines, growth and angiogenic factors) are causally linked to an autocrine pathway that is inhibited after addition of the IL-1 receptor antagonist, Anakinra. In addition, using a human tumor/mouse xenograft model of peritoneal MM, we demonstrate that IL-8, VEGF and IL-6 secretion in peritoneal lavage fluid (PLF) is inhibited by intraperitoneal (ip) injection of Anakinra. Our studies report for the first time the functional importance of inflammasome-mediated cytokine production via an autocrine pathway in mesothelial cells that is perpetuated by durable pathogenic fibers in the pleura. This work is supported by R01 grant (ES021110) from the NIH, and a T32 training grant (ES007122) from the NIEHS.