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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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iNOS protein and mRNA expression in the sera (A) or livers (B and C) 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. β-actin was used as loading control.
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pone-0098660-g003: iNOS protein and mRNA expression in the sera (A) or livers (B and C) 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. β-actin was used as loading control.

Mentions: iNOS catalyzes the formation of NO - the most important RNS [16]. iNOS levels in sera, quantitated by specific ELISA, in control, TCE, NAC or TCE+NAC are presented in Fig. 3A. The levels of iNOS in TCE-treated mice was significantly increased in comparison to the controls, but the increases were attenuated by NAC supplementation. The iNOS protein expression in the livers was also determined by Western blot analysis. The results show that iNOS expression increased significantly in the livers of TCE-treated mice (2.4 folds, Fig. 3B) compared to the controls, and the increases in iNOS expression were attenuated by the NAC supplementation.


Nitrosative stress and nitrated proteins in trichloroethene-mediated autoimmunity.

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

iNOS protein and mRNA expression in the sera (A) or livers (B and C) 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. β-actin was used as loading control.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0098660-g003: iNOS protein and mRNA expression in the sera (A) or livers (B and C) 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. β-actin was used as loading control.
Mentions: iNOS catalyzes the formation of NO - the most important RNS [16]. iNOS levels in sera, quantitated by specific ELISA, in control, TCE, NAC or TCE+NAC are presented in Fig. 3A. The levels of iNOS in TCE-treated mice was significantly increased in comparison to the controls, but the increases were attenuated by NAC supplementation. The iNOS protein expression in the livers was also determined by Western blot analysis. The results show that iNOS expression increased significantly in the livers of TCE-treated mice (2.4 folds, Fig. 3B) compared to the controls, and the increases in iNOS expression were attenuated by the NAC supplementation.

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