Panayota Kolypetri1, George Carayanniotis. 1. Divisions of Endocrinology and Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland , St. John's, Canada .
Abstract
BACKGROUND: Enhanced iodide intake in NOD.H2(h4) mice accelerates the incidence and severity of spontaneous autoimmune thyroiditis (SAT) via an unknown mechanism. A plausible hypothesis is that iodide-induced apoptosis of thyrocytes can create imbalances in antigenic load and/or disruption of immunoregulatory mechanisms that facilitate activation of autoreactive T cells in cervical lymph nodes draining the thyroid. METHODS: We examined whether NOD.H2(h4) thyrocytes, exposed to low NaI concentrations in vitro, are more susceptible to apoptosis compared to thyrocytes from CBA/J mice, which are resistant to iodide-accelerated SAT (ISAT). We also looked, at the transcriptional level, for differential activation of genes involved in apoptosis or oxidative stress pathways that may account for potential differences in iodide-mediated apoptosis between NOD.H2(h4) and CBA/J thyrocytes. RESULTS: We report that NOD.H2(h4) thyrocytes, cultured for 24 h at very low (4-8 μM) concentrations of NaI, exhibit high levels (40-55%) of apoptosis, as assessed microscopically following staining with fluorescent caspase inhibitors. Similar treatment of thyrocytes from CBA/J mice, which are resistant to ISAT, yielded significantly lower (10-20%) apoptotic rates. Expression analysis by real-time polymerase chain reaction using arrays of apoptosis- and oxidative stress-related genes showed that NaI intake upregulates the expression of 22 genes involved in ROS metabolism and/or antioxidant function in CBA/J thyrocytes, whereas only two of these genes were upregulated in NOD.H2(h4) thyrocytes. Among the set of overexpressed genes were those encoding thyroid peroxidase (Tpo; 5.77-fold), glutathione peroxidases (Gpx2, Gpx4, Gpx7; 2.03-3.14-fold), peroxiredoxins (Prdx1, Prdx2, Prdx5; 2.27-2.97-fold), superoxide dismutase 1 (Sod1; 3.57-fold), thioredoxin 1 (Txn1; 2.13-fold), and the uncoupling proteins 2 and 3 (Ucp2, Ucp3; 2.01-2.15-fold). CONCLUSIONS: The results demonstrate that an impaired control of oxidative stress mechanisms is associated with the observed high susceptibility of NOD.H2(h4) thyrocytes to NaI-mediated apoptosis, and suggest a contributing factor for the development of ISAT in this strain.
BACKGROUND: Enhanced iodide intake in NOD.H2(h4) mice accelerates the incidence and severity of spontaneous autoimmune thyroiditis (SAT) via an unknown mechanism. A plausible hypothesis is that iodide-induced apoptosis of thyrocytes can create imbalances in antigenic load and/or disruption of immunoregulatory mechanisms that facilitate activation of autoreactive T cells in cervical lymph nodes draining the thyroid. METHODS: We examined whether NOD.H2(h4) thyrocytes, exposed to low NaI concentrations in vitro, are more susceptible to apoptosis compared to thyrocytes from CBA/J mice, which are resistant to iodide-accelerated SAT (ISAT). We also looked, at the transcriptional level, for differential activation of genes involved in apoptosis or oxidative stress pathways that may account for potential differences in iodide-mediated apoptosis between NOD.H2(h4) and CBA/J thyrocytes. RESULTS: We report that NOD.H2(h4) thyrocytes, cultured for 24 h at very low (4-8 μM) concentrations of NaI, exhibit high levels (40-55%) of apoptosis, as assessed microscopically following staining with fluorescent caspase inhibitors. Similar treatment of thyrocytes from CBA/J mice, which are resistant to ISAT, yielded significantly lower (10-20%) apoptotic rates. Expression analysis by real-time polymerase chain reaction using arrays of apoptosis- and oxidative stress-related genes showed that NaI intake upregulates the expression of 22 genes involved in ROS metabolism and/or antioxidant function in CBA/J thyrocytes, whereas only two of these genes were upregulated in NOD.H2(h4) thyrocytes. Among the set of overexpressed genes were those encoding thyroid peroxidase (Tpo; 5.77-fold), glutathione peroxidases (Gpx2, Gpx4, Gpx7; 2.03-3.14-fold), peroxiredoxins (Prdx1, Prdx2, Prdx5; 2.27-2.97-fold), superoxide dismutase 1 (Sod1; 3.57-fold), thioredoxin 1 (Txn1; 2.13-fold), and the uncoupling proteins 2 and 3 (Ucp2, Ucp3; 2.01-2.15-fold). CONCLUSIONS: The results demonstrate that an impaired control of oxidative stress mechanisms is associated with the observed high susceptibility of NOD.H2(h4) thyrocytes to NaI-mediated apoptosis, and suggest a contributing factor for the development of ISAT in this strain.
Authors: Bronwyn A O'Brien; Xuan Geng; Catherine H Orteu; Yongqian Huang; Mehran Ghoreishi; YiQun Zhang; Jason A Bush; Gang Li; Diane T Finegood; Jan Peter Dutz Journal: J Autoimmun Date: 2006-01-20 Impact factor: 7.094
Authors: A-N Pelletier; H A Aliesky; B Banuelos; G Chabot-Roy; B Rapoport; S Lesage; S M McLachlan Journal: Genes Immun Date: 2015-03-26 Impact factor: 2.676