Asbestos and erionite prime and activate the NLRP3 inflammasome that stimulates autocrine cytokine release in human mesothelial cells

Part Fibre Toxicol. 2013 Aug 13;10:39. doi: 10.1186/1743-8977-10-39.

Abstract

Background: Pleural fibrosis and malignant mesotheliomas (MM) occur after exposures to pathogenic fibers, yet the mechanisms initiating these diseases are unclear.

Results: We document priming and activation of the NLRP3 inflammasome in human mesothelial cells by asbestos and erionite that is causally related to release of IL-1β, IL-6, IL-8, and Vascular Endothelial Growth Factor (VEGF). Transcription and release of these proteins are inhibited in vitro using Anakinra, an IL-1 receptor antagonist that reduces these cytokines in a human peritoneal MM mouse xenograft model.

Conclusions: These novel data show that asbestos-induced priming and activation of the NLRP3 inflammasome triggers an autocrine feedback loop modulated via the IL-1 receptor in mesothelial cell type targeted in pleural infection, fibrosis, and carcinogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asbestos, Crocidolite / toxicity*
  • Autocrine Communication*
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Dose-Response Relationship, Drug
  • Epithelium / drug effects*
  • Epithelium / immunology
  • Epithelium / pathology
  • Humans
  • Inflammasomes / drug effects*
  • Inflammasomes / immunology
  • Inflammation Mediators / metabolism*
  • Interleukin 1 Receptor Antagonist Protein / pharmacology
  • Mesothelioma / chemically induced*
  • Mesothelioma / drug therapy
  • Mesothelioma / genetics
  • Mesothelioma / immunology
  • Mesothelioma / pathology
  • Mice
  • Mice, SCID
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Primary Cell Culture
  • RNA, Messenger / metabolism
  • Receptors, Interleukin-1 / antagonists & inhibitors
  • Receptors, Interleukin-1 / metabolism
  • Time Factors
  • Transcription, Genetic / drug effects
  • Xenograft Model Antitumor Assays
  • Zeolites / toxicity*

Substances

  • Carrier Proteins
  • Cytokines
  • Inflammasomes
  • Inflammation Mediators
  • Interleukin 1 Receptor Antagonist Protein
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • RNA, Messenger
  • Receptors, Interleukin-1
  • Asbestos, Crocidolite
  • erionite
  • Zeolites