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.
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.
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.
authors.forename: Gangduo
authors.initials: G
authors.lastname: Wang
authors.forename: Jianling
authors.initials: J
authors.lastname: Wang
authors.forename: Xiuzhen
authors.initials: X
authors.lastname: Fan
authors.forename: G A S
authors.initials: GA
authors.lastname: Ansari
authors.forename: M Firoze
authors.initials: MF
authors.lastname: Khan
mesh_terms: D000447:Aldehydes / Q000276:immunology*; D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D007668:Kidney / Q000201:enzymology; D008315:Malondialdehyde / Q000276:immunology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D012997:Solvents; D018709:Statistics, Nonparametric; D014241:Trichloroethylene / Q000633:toxicity*; D000098546:Interleukin-21
chemical_list: D000447:Aldehydes; D020381:Interleukin-17; D007378:Interleukins; D012997:Solvents; D014241:Trichloroethylene; D008315:Malondialdehyde; D005978:Glutathione; C027576:4-hydroxy-2-nonenal; D000098546:Interleukin-21