Functional expression of system x(c)- is upregulated by asbestos but not crystalline silica in murine macrophages

Inhal Toxicol. 2012 Jul;24(8):476-85. doi: 10.3109/08958378.2012.689782. Epub 2012 Jun 14.


Context: Inhalation of asbestos or silica is associated with chronic and progressive diseases, including fibrosis, cancer, and increased risk of systemic autoimmunity. Because there is a need for treatment options for these diseases, a better understanding of their mechanistic etiologies is essential. While oxidative stress in macrophages is an early consequence of these exposures, it may also serve as a signaling mechanism involved in downstream immune dysregulation. The system x(c)(-) exchange protein is induced by oxidative stress, and exchanges equimolor levels of extracellular cystine for intracellular glutamate. Cystine is subsequently reduced to cysteine, the rate-limiting precursor for glutathione synthesis.

Objective: As the primary transporter responsible for cystine/glutamate exchange on macrophages, system x(c)- was hypothesized to be inducible in response to asbestos and silica, and to increase viability through protection from oxidative stress.

Results: When challenged with amphibole asbestos, but not crystalline silica, RAW 264.7 macrophages increased expression of xCT and the rate of cystine/glutamate exchange in sodium-free conditions. This upregulation was prevented with N-acetylcysteine, implicating oxidative stress. Cystine protected the macrophages from asbestos-induced oxidative stress and cell death, supporting the hypothesis that imported cystine was used for synthesis of cellular antioxidants. System x(c)(-) inhibitors, glutamate and S-4-carboxyphenylglycine ((S)-4-CPG), significantly increased oxidative stress and cell death of asbestos-treated macrophages.

Conclusion: System x(c)(-) plays a critical role in survival of macrophages exposed to asbestos, but not silica. These data demonstrate a very early difference in the cellular response to these silicates that may have important downstream implications in the pathologic outcome of exposure.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Transport System y+ / biosynthesis*
  • Animals
  • Asbestos, Amphibole / toxicity*
  • Asbestos, Crocidolite / toxicity*
  • Biological Transport
  • Calcium Compounds / toxicity
  • Cell Culture Techniques
  • Cell Line
  • Cell Survival / drug effects
  • Cysteine / metabolism
  • Dose-Response Relationship, Drug
  • Flow Cytometry
  • Glutamic Acid / metabolism
  • Glutathione / metabolism
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Mice
  • Protein Subunits
  • Silicates / toxicity
  • Silicon Dioxide / toxicity*
  • Up-Regulation


  • Amino Acid Transport System y+
  • Asbestos, Amphibole
  • Calcium Compounds
  • Protein Subunits
  • Silicates
  • Slc7a11 protein, mouse
  • Asbestos, Crocidolite
  • Glutamic Acid
  • Silicon Dioxide
  • Glutathione
  • Cysteine
  • calcium silicate