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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 plausible mechanisms of TCE-induced autoimmune response and its attenuation by NAC supplementation.
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pone-0098660-g006: The plausible mechanisms of TCE-induced autoimmune response and its attenuation by NAC supplementation.

Mentions: It is evident from our data that TCE exposure also resulted in an increased expression and activation of NF-κB p65. Interestingly, NAC supplementation not only ameliorated the TCE-induced nitrosative stress, GSH and NF-κB p65 activation, but also the markers of autoimmune response, as evident from decreased levels of autoantibodies in the sera. NAC treatment can reduce the formation of ONOO- possibly by a simultaneous inhibition of ROS and NO via the suppression of NF-κB-mediated induction of iNOS expression [29], [33], [53]. Based on these findings, we conclude that TCE exposure activated iNOS and generated free radicals (RONS) leading to increased ONOO-, which led to increased formation of modified proteins (NT or nitrated proteins) which can act as immunogen or neoantigens. These immunogen/neoantigens might activate lymphocytes or cause break in immune tolerance, leading to autoimmune response [6]-[8], [21]. NAC supplementation could ameliorate TCE-induced autoimmunity potentially via suppressing/averting NF-κB and iNOS activity or by directly scavenging free radicals (O2.-, NO and ONOO-) leading to reduction in neoantigen formation and thus, an autoimmune response [29], [32], [33], [54], [55]. Fig. 6 depicts the potential pathways of TCE-induced autoimmunity and its attenuation following NAC supplementation. Our results thus, not only provide support to the role of nitrosative stress in TCE-induced autoimmune response, but also provide a map for further investigating alterations in these nitrated proteins' structural and functional properties, which could lead to a better understanding of the role of protein nitration in the pathogenesis of TCE-mediated autoimmunity. Attenuation of TCE-induced autoimmunity in mice by NAC could be important in developing preventive and/or therapeutic strategies.


Nitrosative stress and nitrated proteins in trichloroethene-mediated autoimmunity.

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

The plausible mechanisms of TCE-induced autoimmune response and its attenuation by NAC supplementation.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0098660-g006: The plausible mechanisms of TCE-induced autoimmune response and its attenuation by NAC supplementation.
Mentions: It is evident from our data that TCE exposure also resulted in an increased expression and activation of NF-κB p65. Interestingly, NAC supplementation not only ameliorated the TCE-induced nitrosative stress, GSH and NF-κB p65 activation, but also the markers of autoimmune response, as evident from decreased levels of autoantibodies in the sera. NAC treatment can reduce the formation of ONOO- possibly by a simultaneous inhibition of ROS and NO via the suppression of NF-κB-mediated induction of iNOS expression [29], [33], [53]. Based on these findings, we conclude that TCE exposure activated iNOS and generated free radicals (RONS) leading to increased ONOO-, which led to increased formation of modified proteins (NT or nitrated proteins) which can act as immunogen or neoantigens. These immunogen/neoantigens might activate lymphocytes or cause break in immune tolerance, leading to autoimmune response [6]-[8], [21]. NAC supplementation could ameliorate TCE-induced autoimmunity potentially via suppressing/averting NF-κB and iNOS activity or by directly scavenging free radicals (O2.-, NO and ONOO-) leading to reduction in neoantigen formation and thus, an autoimmune response [29], [32], [33], [54], [55]. Fig. 6 depicts the potential pathways of TCE-induced autoimmunity and its attenuation following NAC supplementation. Our results thus, not only provide support to the role of nitrosative stress in TCE-induced autoimmune response, but also provide a map for further investigating alterations in these nitrated proteins' structural and functional properties, which could lead to a better understanding of the role of protein nitration in the pathogenesis of TCE-mediated autoimmunity. Attenuation of TCE-induced autoimmunity in mice by NAC could be important in developing preventive and/or therapeutic strategies.

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