Functional expression of system xc − is upregulated by asbestos but not crystalline silica in murine macrophages
Source: Inhalation Toxicology, Volume 24, Number 8, July 2012 , pp. 476-485(10)
Publisher: Informa Healthcare
Abstract: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 xc − 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 xc− 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 xc − inhibitors, glutamate and S-4-carboxyphenylglycine ((S)-4-CPG), significantly increased oxidative stress and cell death of asbestos-treated macrophages.
Conclusion: System xc − 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.
Document Type: Research Article
Publication date: July 2012