De Bleecker Jan L, De Paepe Boel, Vervaet Veerle L, Arys Bo, Creus Kim K, Werbrouck Bart F, Martin Jean-Jacques
Department of Neurology, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, Belgium.
Neuromuscul Disord. 2007 Feb;17(2):186-93. doi: 10.1016/j.nmd.2006.11.004. Epub 2007 Jan 23.
In contrast with dermatomyositis and polymyositis, inclusion body myositis is unresponsive to glucocorticoid treatment. Glucocorticoid action is mediated through an active glucocorticoid receptor-alpha and negatively regulated by another glucocorticoid receptor isoform. In several autoimmune diseases glucocorticoid receptor-beta up-regulation is involved in glucocorticoid resistance. We studied glucocorticoid receptor distribution in normal and inflammatory myopathy muscle and investigated whether differences in glucocorticoid receptor-alpha and glucocorticoid receptor-beta protein expression are involved in the differential glucocorticoid sensitivity in inclusion body myositis versus polymyositis. Multistep immunofluorescence and Western blotting on fractionated cytoplasmic or nuclear muscle samples were used. Glucocorticoid receptor-alpha was the predominant receptor subtype in muscle and occurred abundantly in myonuclei of control and diseased muscle alike. Glucocorticoid receptor-beta was constitutively expressed on a subset of endothelial cells. No differences between dermatomyositis and the other idiopathic inflammatory myopathies were observed. Increased nuclear glucocorticoid receptor that has dissociated from heat shock protein 90 was found in glucocorticoid treated subjects. Glucocorticoid receptor-alpha and -beta isoform levels were unaltered in muscle tissues from control subjects that had received glucocorticoid treatment prior to biopsy. No differences in relative glucocorticoid receptor-alpha and glucocorticoid receptor-beta protein expression were seen in inclusion body myositis versus polymyositis specimens. Our study indicates that the different glucocorticoid sensitivity in the idiopathic inflammatory myopathies is not related to up- or down-regulation of a given glucocorticoid receptor isoform at the protein level.
与皮肌炎和多发性肌炎不同，包涵体肌炎对糖皮质激素治疗无反应。糖皮质激素的作用是通过活性糖皮质激素受体α介导的，并受到另一种糖皮质激素受体异构体的负调控。在几种自身免疫性疾病中，糖皮质激素受体β的上调与糖皮质激素抵抗有关。我们研究了正常和炎性肌病肌肉中糖皮质激素受体的分布，并调查了糖皮质激素受体α和糖皮质激素受体β蛋白表达的差异是否与包涵体肌炎和多发性肌炎中糖皮质激素敏感性的差异有关。我们使用了对分离的细胞质或细胞核肌肉样本进行的多步免疫荧光和蛋白质印迹法。糖皮质激素受体α是肌肉中的主要受体亚型，在对照和患病肌肉的肌核中均大量存在。糖皮质激素受体β在一部分内皮细胞上组成性表达。未观察到皮肌炎与其他特发性炎性肌病之间存在差异。在接受糖皮质激素治疗的受试者中发现与热休克蛋白90解离的核糖皮质激素受体增加。在活检前接受过糖皮质激素治疗的对照受试者的肌肉组织中，糖皮质激素受体α和β异构体水平未改变。在包涵体肌炎与多发性肌炎标本中，未观察到相对糖皮质激素受体α和糖皮质激素受体β蛋白表达的差异。我们的研究表明，特发性炎性肌病中不同的糖皮质激素敏感性与蛋白质水平上特定糖皮质激素受体异构体的上调或下调无关。
