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Nitrosative stress and nitrated proteins in trichloroethene-mediated autoimmunity.

Wang G, Wang J, Luo X, Ansari GA, Khan MF - PLoS ONE (2014)

Bottom Line: TCE exposure led to significant increases in serum anti-nuclear and anti-histone antibodies together with significant induction of iNOS and increased formation of nitrotyrosine (NT) in sera and livers.Furthermore, TCE exposure led to decreased GSH levels and increased activation of NF-κB.These findings provide support to the role of nitrosative stress in TCE-mediated autoimmune response and identify specific nitrated proteins which could have autoimmune potential.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.

ABSTRACT
Exposure to trichloroethene (TCE), a ubiquitous environmental contaminant, has been linked to a variety of autoimmune diseases (ADs) including SLE, scleroderma and hepatitis. Mechanisms involved in the pathogenesis of ADs are largely unknown. Earlier studies from our laboratory in MRL+/+ mice suggested the contribution of oxidative/nitrosative stress in TCE-induced autoimmunity, and N-acetylcysteine (NAC) supplementation provided protection by attenuating oxidative stress. This study was undertaken to further evaluate the contribution of nitrosative stress in TCE-mediated autoimmunity and to identify proteins susceptible to nitrosative stress. Groups of female MRL +/+ mice were given TCE, NAC or TCE + NAC for 6 weeks (TCE, 10 mmol/kg, i.p., every 4th day; NAC, ∼ 250 mg/kg/day via drinking water). TCE exposure led to significant increases in serum anti-nuclear and anti-histone antibodies together with significant induction of iNOS and increased formation of nitrotyrosine (NT) in sera and livers. Proteomic analysis identified 14 additional nitrated proteins in the livers of TCE-treated mice. Furthermore, TCE exposure led to decreased GSH levels and increased activation of NF-κB. Remarkably, NAC supplementation not only ameliorated TCE-induced nitrosative stress as evident from decreased iNOS, NT, nitrated proteins, NF-κB p65 activation and increased GSH levels, but also the markers of autoimmunity, as evident from decreased levels of autoantibodies in the sera. These findings provide support to the role of nitrosative stress in TCE-mediated autoimmune response and identify specific nitrated proteins which could have autoimmune potential. Attenuation of TCE-induced autoimmunity in mice by NAC provides an approach for designing therapeutic strategies.

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The formation of nitrotyrosine in the sera (A) or livers (B) of MRL+/+ mice treated with TCE, NAC or TCE+NAC for 6 weeks.The values are means ± SD. *p<0.05 vs. controls; #p<0.05 vs. TCE-treated mice.
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pone-0098660-g002: The formation of nitrotyrosine in the sera (A) or livers (B) of MRL+/+ mice treated with TCE, NAC or TCE+NAC for 6 weeks.The values are means ± SD. *p<0.05 vs. controls; #p<0.05 vs. TCE-treated mice.

Mentions: NT formation is considered to be a biomarker of RNS production [4], [9], [19]. To assess the involvement of nitrosative stress in TCE-mediated autoimmune response, we determined the serum levels of NT in control and TCE, NAC or TCE+NAC-treated mice. Fig. 2 shows that TCE exposure led to significant increases in serum NT levels, which were attenuated by NAC supplementation (Fig. 2A). The NT levels in liver, a major organ where TCE is known to generate free radicals and lead to autoimmune damages [26], [39], [44], [48], were also analyzed. The NT levels in livers were also significantly higher in TCE-treated mice in comparison to the controls and NAC supplementation attenuated the increases in NT (Fig. 2B).


Nitrosative stress and nitrated proteins in trichloroethene-mediated autoimmunity.

Wang G, Wang J, Luo X, Ansari GA, Khan MF - PLoS ONE (2014)

The formation of nitrotyrosine in the sera (A) or livers (B) of MRL+/+ mice treated with TCE, NAC or TCE+NAC for 6 weeks.The values are means ± SD. *p<0.05 vs. controls; #p<0.05 vs. TCE-treated mice.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4043737&req=5

pone-0098660-g002: The formation of nitrotyrosine in the sera (A) or livers (B) of MRL+/+ mice treated with TCE, NAC or TCE+NAC for 6 weeks.The values are means ± SD. *p<0.05 vs. controls; #p<0.05 vs. TCE-treated mice.
Mentions: NT formation is considered to be a biomarker of RNS production [4], [9], [19]. To assess the involvement of nitrosative stress in TCE-mediated autoimmune response, we determined the serum levels of NT in control and TCE, NAC or TCE+NAC-treated mice. Fig. 2 shows that TCE exposure led to significant increases in serum NT levels, which were attenuated by NAC supplementation (Fig. 2A). The NT levels in liver, a major organ where TCE is known to generate free radicals and lead to autoimmune damages [26], [39], [44], [48], were also analyzed. The NT levels in livers were also significantly higher in TCE-treated mice in comparison to the controls and NAC supplementation attenuated the increases in NT (Fig. 2B).

Bottom Line: TCE exposure led to significant increases in serum anti-nuclear and anti-histone antibodies together with significant induction of iNOS and increased formation of nitrotyrosine (NT) in sera and livers.Furthermore, TCE exposure led to decreased GSH levels and increased activation of NF-κB.These findings provide support to the role of nitrosative stress in TCE-mediated autoimmune response and identify specific nitrated proteins which could have autoimmune potential.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.

ABSTRACT
Exposure to trichloroethene (TCE), a ubiquitous environmental contaminant, has been linked to a variety of autoimmune diseases (ADs) including SLE, scleroderma and hepatitis. Mechanisms involved in the pathogenesis of ADs are largely unknown. Earlier studies from our laboratory in MRL+/+ mice suggested the contribution of oxidative/nitrosative stress in TCE-induced autoimmunity, and N-acetylcysteine (NAC) supplementation provided protection by attenuating oxidative stress. This study was undertaken to further evaluate the contribution of nitrosative stress in TCE-mediated autoimmunity and to identify proteins susceptible to nitrosative stress. Groups of female MRL +/+ mice were given TCE, NAC or TCE + NAC for 6 weeks (TCE, 10 mmol/kg, i.p., every 4th day; NAC, ∼ 250 mg/kg/day via drinking water). TCE exposure led to significant increases in serum anti-nuclear and anti-histone antibodies together with significant induction of iNOS and increased formation of nitrotyrosine (NT) in sera and livers. Proteomic analysis identified 14 additional nitrated proteins in the livers of TCE-treated mice. Furthermore, TCE exposure led to decreased GSH levels and increased activation of NF-κB. Remarkably, NAC supplementation not only ameliorated TCE-induced nitrosative stress as evident from decreased iNOS, NT, nitrated proteins, NF-κB p65 activation and increased GSH levels, but also the markers of autoimmunity, as evident from decreased levels of autoantibodies in the sera. These findings provide support to the role of nitrosative stress in TCE-mediated autoimmune response and identify specific nitrated proteins which could have autoimmune potential. Attenuation of TCE-induced autoimmunity in mice by NAC provides an approach for designing therapeutic strategies.

Show MeSH
Related in: MedlinePlus