Asbestos is the main cause of human
malignant mesothelioma (MM). In vivo, macrophages phagocytize
asbestos and, in response, release
TNF-alpha and other
cytokines that contribute to
carcinogenesis through unknown mechanisms. In vitro,
asbestos does not induce transformation of primary human mesothelial cells (HM); instead,
asbestos is very cytotoxic to HM, causing extensive cell death. This finding raised an apparent paradox: How can
asbestos cause MM if HM exposed to
asbestos die? We found that
asbestos induced the secretion of
TNF-alpha and the expression of
TNF-alpha receptor I in HM. Treatment of HM with
TNF-alpha significantly reduced
asbestos cytotoxicity. Through numerous technical approaches, including chemical inhibitors and
small interfering RNA strategies, we demonstrate that, in HM,
TNF-alpha activates
NF-kappaB and that
NF-kappaB activation leads to HM survival and resistance to the cytotoxic effects of
asbestos. Our data show a critical role for
TNF-alpha and
NF-kappaB signaling in mediating HM responses to
asbestos.
TNF-alpha signaling through
NF-kappaB-dependent mechanisms increases the percent of HM that survives
asbestos exposure, thus increasing the pool of
asbestos-damaged HM that are susceptible to malignant transformation. Cytogenetics supported this hypothesis, showing only rare, aberrant metaphases in HM exposed to
asbestos and an increased mitotic rate with fewer irregular metaphases in HM exposed to both
TNF-alpha and
asbestos. Our findings provide a mechanistic rationale for the paradoxical inability of
asbestos to transform HM in vitro, elucidate and underscore the role of
TNF-alpha in
asbestos pathogenesis in humans, and identify potential molecular targets for anti-MM prevention and
therapy.