INOS Contributes to Trichloroethene‐Mediated Autoimmunity

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Reactive nitrogen species (RNS) have been implicated in the pathogenesis of autoimmune diseases (ADs). However, the potential mechanisms by which RNS contribute to the pathogenesis of ADs remain largely unexplored. Earlier studies from our laboratory in MRL+/+ mice suggested a role of RNS in trichloroethene (TCE)‐mediated autoimmunity. To further evaluate the contribution of nitrosative stress, especially iNOS, in TCE‐mediated autoimmunity, we conducted studies in iNOS‐null MRL+/+ mice. iNOS‐null MRL+/+ mice were obtained by backcrossing iNOS‐null mice to MRL +/+ mice. Female MRL+/+ and iNOS‐null MRL+/+ mice were treated with TCE (10 mmol/kg, i.p., in corn oil, every 4th day) for 6 weeks; their respective controls received corn oil only. TCE exposure in MRL+/+ mice led to significantly increased iNOS mRNA in livers, iNOS protein in livers and sera, and increased formation of nitrotyrosine (NT) in both sera and livers. These increases were associated with significant increases in serum anti‐double stranded DNA (anti‐dsDNA) and anti‐nuclear antibodies (ANA). Expectedly, iNOS levels and NT formation were negligible in both iNOS‐null controls and TCE‐treated iNOS‐null MRL+/+ mice. Even though TCE treatment still led to increases in serum anti‐dsDNA and ANA in iNOS‐null MRL+/+ mice compared to untreated controls, interestingly, the increases in serum anti‐dsDNA and ANA induced by TCE in the iNOS‐null MRL+/+ mice were significantly less pronounced compared to that in MRL+/+ mice. The observed differential autoimmune responses to TCE exposure in MRL+/+ vs. iNOS‐null MRL+/+ mice further support the contribution of iNOS and RNS in TCE‐mediated autoimmunity.