title: iNOS null MRL+/+ mice show attenuation of trichloroethene-mediated autoimmunity: contribution of reactive nitrogen species and lipid-derived reactive aldehydes.
abstract: Earlier studies from our laboratory in MRL+/+ mice suggest that free radicals, especially overproduction of reactive nitrogen species (RNS) and lipid-derived reactive aldehydes (LDRAs), are associated with trichloroethene (TCE)-mediated autoimmune response. The current study was undertaken to further assess the contribution of RNS and LDRAs in TCE-mediated autoimmunity by using iNOS-null MRL+/+ mice. iNOS-null MRL+/+ mice were obtained by backcrossing iNOS-null mice (B6.129P2-Nos2(tm1Lau)/J) to MRL +/+ mice. Female MRL+/+ and iNOS-null MRL+/+ mice were given TCE (10 mmol/kg, i.p., every 4(th) day) for 6 weeks; their respective controls received corn oil only. TCE exposure led to significantly increased iNOS mRNA in livers, iNOS protein in livers and sera, increased nitrotyrosine (NT) formation in both livers and sera, induction of MDA-/HNE-protein adducts in livers and their respective antibodies in sera along with significant increases in serum antinuclear antibodies (ANA) and anti-dsDNA in MRL+/+ mice. Even though in iNOS-null MRL+/+ mice, the iNOS and NT levels were negligible in both TCE-treated and untreated groups, TCE treatment still led to significant increases in MDA-/HNE-protein adducts and their respective antibodies along with increases in serum ANA and anti-dsDNA compared to controls. Most remarkably, the increases in serum ANA and anti-dsDNA induced by TCE in the iNOS-null MRL+/+ mice were significantly less pronounced compared to that in MRL+/+ mice. Our results provide further evidence that both RNS and LDRAs contribute to TCE-induced autoimmunity in MRL+/+ mice, and iNOS deficiency attenuates this autoimmune response.
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555.
authors.forename: Gangduo
authors.initials: G
authors.lastname: Wang
authors.affiliation: Transgenic Mouse Core Facility, Institute for Translational Sciences and Animal Resource Center.
authors.forename: Maki
authors.initials: M
authors.lastname: Wakamiya
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555.
authors.forename: Jianling
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555.
authors.forename: G A S
authors.initials: GA
authors.lastname: Ansari
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555. Electronic address: mfkhan@utmb.edu.
authors.forename: M
authors.initials: M
authors.lastname: Firoze Khan
mesh_terms: D000447:Aldehydes / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D015551:Autoimmunity / Q000502:physiology*; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D050356:Lipid Metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000276:immunology / Q000378:metabolism*; D026361:Reactive Nitrogen Species / Q000276:immunology / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014241:Trichloroethylene / Q000633:toxicity*
chemical_list: D000447:Aldehydes; D026361:Reactive Nitrogen Species; D014241:Trichloroethylene; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: Autoantibody; Autoimmunity; Free radical; INOS; Trichloroethene