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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 levels of GSH 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-g001: The levels of GSH 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: Glutathione (GSH), an endogenous antioxidant, prevents damage to cellular components caused by reactive oxygen species [28], [42], [43]. TCE is known to generate free radicals [3], [8], [27], [44], [45] and NAC is a precursor of GSH. To assess the redox status following TCE, NAC or TCE+NAC exposure and evaluate the contribution of ROS/RNS in TCE-induced autoimmunity, the glutathione level was quantitated in the sera and livers. As evident from Fig. 1, TCE exposure caused significant decreases in GSH levels both in the sera and livers as compared to the controls. However, NAC supplementation attenuated the GSH levels as evident from significantly increased GSH levels in mice treated with TCE+NAC as compared to TCE only group.


Nitrosative stress and nitrated proteins in trichloroethene-mediated autoimmunity.

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

The levels of GSH 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-g001: The levels of GSH 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: Glutathione (GSH), an endogenous antioxidant, prevents damage to cellular components caused by reactive oxygen species [28], [42], [43]. TCE is known to generate free radicals [3], [8], [27], [44], [45] and NAC is a precursor of GSH. To assess the redox status following TCE, NAC or TCE+NAC exposure and evaluate the contribution of ROS/RNS in TCE-induced autoimmunity, the glutathione level was quantitated in the sera and livers. As evident from Fig. 1, TCE exposure caused significant decreases in GSH levels both in the sera and livers as compared to the controls. However, NAC supplementation attenuated the GSH levels as evident from significantly increased GSH levels in mice treated with TCE+NAC as compared to TCE only group.

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