TY - JOUR
T1 - Endoplasmic reticulum stress as a novel mechanism in amiodaroneinduced destructive thyroiditis
AU - Lombardi, Angela
AU - Inabnet, William Barlow
AU - Owen, Randall
AU - Farenholtz, Kaitlyn Ellen
AU - Tomer, Yaron
N1 - Publisher Copyright:
© 2015 by the Endocrine Society.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - Context: Amiodarone (AMIO) is one of the most effective antiarrhythmic drugs available; however, its use is limited by a serious side effect profile, including thyroiditis. The mechanisms underlying AMIO thyroid toxicity have been elusive; thus, identification of novel approaches in order to prevent thyroiditis is essential in patients treated with AMIO. Objective: Our aim was to evaluate whether AMIO treatment could induce endoplasmic reticulum (ER) stress in human thyroid cells and the possible implications of this effect in AMIO-induced destructive thyroiditis. Results: Here we report that AMIO, but not iodine, significantly induced the expression of ER stress markersincluding Igheavychain-binding protein (BiP), phosphoeukaryotic translation initiation factor 2α(eIF2α), CCAAT/enhancer-binding protein homologous protein (CHOP) and spliced X-box binding protein-1 (XBP-1) in human thyroid ML-1 cells and human primary thyrocytes. In both experimental systems AMIO down-regulated thyroglobulin (Tg) protein but had little effect on Tg mRNA levels, suggesting a mechanism involving Tg protein degradation. Indeed, pretreatment with the specific proteasome inhibitor MG132 reversed AMIO-induced down-regulation of Tg protein levels, confirming a proteasome-dependent degradation of Tg protein. Corroborating our findings, pretreatment of ML-1cellsandhumanprimarythyrocyteswiththechemicalchaperone4-phenylbutyric acidcompletely prevented the effect of AMIO on both ER stress induction and Tg down-regulation. Conclusions: We identified ER stress as a novel mechanism contributing to AMIO-induced destructive thyroiditis. Our data establish that AMIO-induced ER stress impairs Tg expression via proteasome activation, providing a valuable therapeutic avenue for the treatment of AMIO-induced destructive thyroiditis.
AB - Context: Amiodarone (AMIO) is one of the most effective antiarrhythmic drugs available; however, its use is limited by a serious side effect profile, including thyroiditis. The mechanisms underlying AMIO thyroid toxicity have been elusive; thus, identification of novel approaches in order to prevent thyroiditis is essential in patients treated with AMIO. Objective: Our aim was to evaluate whether AMIO treatment could induce endoplasmic reticulum (ER) stress in human thyroid cells and the possible implications of this effect in AMIO-induced destructive thyroiditis. Results: Here we report that AMIO, but not iodine, significantly induced the expression of ER stress markersincluding Igheavychain-binding protein (BiP), phosphoeukaryotic translation initiation factor 2α(eIF2α), CCAAT/enhancer-binding protein homologous protein (CHOP) and spliced X-box binding protein-1 (XBP-1) in human thyroid ML-1 cells and human primary thyrocytes. In both experimental systems AMIO down-regulated thyroglobulin (Tg) protein but had little effect on Tg mRNA levels, suggesting a mechanism involving Tg protein degradation. Indeed, pretreatment with the specific proteasome inhibitor MG132 reversed AMIO-induced down-regulation of Tg protein levels, confirming a proteasome-dependent degradation of Tg protein. Corroborating our findings, pretreatment of ML-1cellsandhumanprimarythyrocyteswiththechemicalchaperone4-phenylbutyric acidcompletely prevented the effect of AMIO on both ER stress induction and Tg down-regulation. Conclusions: We identified ER stress as a novel mechanism contributing to AMIO-induced destructive thyroiditis. Our data establish that AMIO-induced ER stress impairs Tg expression via proteasome activation, providing a valuable therapeutic avenue for the treatment of AMIO-induced destructive thyroiditis.
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U2 - 10.1210/jc.2014-2745
DO - 10.1210/jc.2014-2745
M3 - Article
C2 - 25295624
AN - SCOPUS:84920570441
SN - 0021-972X
VL - 100
SP - E1-E10
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 1
ER -