Title: Protein adducts of malondialdehyde and 4-hydroxynonenal contribute to trichloroethene-mediated autoimmunity via activating Th17 cells: dose- and time-response studies in female MRL+/+ mice.
Authors: Wang, Gangduo; Wang, Jianling; Fan, Xiuzhen; Ansari, G A S; Khan, M Firoze
Published In Toxicology, (2012 Feb 26)
Abstract: Trichloroethene (TCE), a common occupational and environmental toxicant, is known to induce autoimmunity. Previous studies in our laboratory showed increased oxidative stress in TCE-mediated autoimmunity. To further establish the role of oxidative stress and to investigate the mechanisms of TCE-mediated autoimmunity, dose- and time-response studies were conducted in MRL+/+ mice by treating them with TCE via drinking water at doses of 0.5, 1.0 or 2.0mg/ml for 12, 24 or 36 weeks. TCE exposure led to dose-related increases in malondialdehyde (MDA)-/hydroxynonenal (HNE)-protein adducts and their corresponding antibodies in the sera and decreases in GSH and GSH/GSSG ratio in the kidneys at 24 and 36 weeks, with greater changes at 36 weeks. The increases in these protein adducts and decreases in GSH/GSSG ratio were associated with significant elevation in serum anti-nuclear- and anti-ssDNA-antibodies, suggesting an association between TCE-induced oxidative stress and autoimmune response. Interestingly, splenocytes from mice treated with TCE for 24 weeks secreted significantly higher levels of IL-17 and IL-21 than did splenocytes from controls after stimulation with MDA-mouse serum albumin (MSA) or HNE-MSA adducts. The increased release of these cytokines showed a dose-related response and was more pronounced in mice treated with TCE for 36 weeks. These studies provide evidence that MDA- and or HNE-protein adducts contribute to TCE-mediated autoimmunity, which may be via activation of Th17 cells.
PubMed ID: 22178267
MeSH Terms: Aldehydes/immunology*; Animals; Autoimmune Diseases/chemically induced*; Autoimmune Diseases/immunology; Autoimmunity/drug effects; Dose-Response Relationship, Drug; Female; Glutathione/immunology; Interleukin-17/immunology; Interleukins/immunology; Kidney/enzymology; Malondialdehyde/immunology*; Mice; Mice, Inbred MRL lpr; Solvents; Statistics, Nonparametric; Trichloroethylene/toxicity*