Increased nitration and carbonylation of proteins in MRL +/+ mice exposed to trichloroethene: Potential role of protein oxidation in autoimmunity

• Published in: Toxicology and applied pharmacology Vol. 237; no. 2; pp. 188 - 195
• Main Authors: Wang, Gangduo, Wang, Jianling, Ma, Huaxian, Khan, M. Firoze
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.06.2009; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Autoimmune Diseases; Autoimmune Diseases - chemically induced; Biological and medical sciences; CARBONYLATION; Cells, Cultured; Cytokines - metabolism; DISEASES; Drug Administration Schedule; Female; Gene Expression Regulation - drug effects; iNOS; Kidney - drug effects; Kidney - metabolism; KIDNEYS; LIVER; Liver - drug effects; Liver - metabolism; Medical sciences; MICE; Mice, Inbred MRL lpr; NITRATION; Nitric Oxide Synthase Type II - metabolism; ORGANIC CHLORINE COMPOUNDS; OXIDATION; Oxidation-Reduction; Oxidative Stress - drug effects; PATHOGENESIS; Protein Carbonylation - drug effects; PROTEINS; Spleen - cytology; Toxicology; Trichloroethene; Trichloroethylene - administration & dosage; Trichloroethylene - toxicity; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Nitration; Trichloroethene; iNOS; Carbonylation; Autoimmune Diseases; Autoimmunity; Immunopathology; Enzyme; Rodentia; Autoimmune disease; Nitric-oxide synthase; Protein; Vertebrata; Mammalia; Mouse; Animal; Oxidation; Oxidoreductases
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2009.03.010

Even though reactive oxygen and nitrogen species (RONS) are implicated as mediators of autoimmune diseases (ADs), little is known about contribution of protein oxidation (carbonylation and nitration) in the pathogenesis of such diseases. The focus of this study was, therefore, to establish a link between protein oxidation and induction and/or exacerbation of autoimmunity. To achieve this, female MRL +/+ mice were treated with trichloroethene (TCE), an environmental contaminant known to induce autoimmune response, for 6 or 12 weeks (10 mmol/kg, i.p., every 4 th day). TCE treatment resulted in significantly increased formation of nitrotyrosine (NT) and induction of iNOS in the serum at both 6 and 12 weeks of treatment, but the response was greater at 12 weeks. Likewise, TCE treatment led to greater NT formation, and iNOS protein and mRNA expression in the livers and kidneys. Moreover, TCE treatment also caused significant increases (∼3 fold) in serum protein carbonyls (a marker of protein oxidation) at both 6 and 12 weeks. Significantly increased protein carbonyls were also observed in the livers and kidneys (2.1 and 1.3 fold, respectively) at 6 weeks, and to a greater extent at 12 weeks (3.5 and 2.1 fold, respectively) following TCE treatment. The increases in TCE-induced protein oxidation (carbonylation and nitration) were associated with significant increases in Th1 specific cytokine (IL-2, IFN-γ) release into splenocyte cultures. These results suggest an association between protein oxidation and induction/exacerbation of autoimmune response. The results present a potential mechanism by which oxidatively modified proteins could contribute to TCE-induced autoimmune response and necessitates further investigations for clearly establishing the role of protein oxidation in the pathogenesis of ADs.