title: TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis.
abstract: 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.
authors.affiliation: *Thoracic Oncology Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153.
authors.forename: Haining
authors.initials: H
authors.lastname: Yang
authors.affiliation: *Thoracic Oncology Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bocchetta
authors.affiliation: *Thoracic Oncology Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kroczynska
authors.affiliation: *Thoracic Oncology Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153.
authors.forename: Amira G
authors.initials: AG
authors.lastname: Elmishad
authors.affiliation: *Thoracic Oncology Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153.
authors.forename: Yuanbin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Zemin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: The Ben May Institute for Cancer Research, University of Chicago, Chicago, IL 60637.
authors.forename: Concetta
authors.initials: C
authors.lastname: Bubici
authors.affiliation: Department of Pathology, College of Medicine, University of Vermont, Burlington, VT 05404; and.
authors.forename: Brooke T
authors.initials: BT
authors.lastname: Mossman
authors.affiliation: Division of Thoracic Surgery, New York University, New York, NY 10016.
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.affiliation: Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Testa
authors.affiliation: The Ben May Institute for Cancer Research, University of Chicago, Chicago, IL 60637.
authors.forename: Guido
authors.initials: G
authors.lastname: Franzoso
authors.affiliation: *Thoracic Oncology Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153; mcarbone@crch.hawaii.edu.
authors.forename: Michele
authors.initials: M
authors.lastname: Carbone
mesh_terms: D001194:Asbestos / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D002877:Chromosomes, Human / Q000235:genetics; D004848:Epithelium / Q000187:drug effects; D006801:Humans; D008677:Metaphase; D016328:NF-kappa B / Q000378:metabolism*; D034622:RNA Interference; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D001194:Asbestos