Distribution of glucocorticoid receptor alpha and beta subtypes in the idiopathic inflammatory myopathies.
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.
De Bleecker
Jan L
JL
Department of Neurology, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, Belgium. jan.debleecker@Ugent.be
De Paepe
Boel
B
Vervaet
Veerle L
VL
Arys
Bo
B
Creus
Kim K
KK
Werbrouck
Bart F
BF
Martin
Jean-Jacques
JJ
D001808:Blood Vessels / Q000378:metabolism; D015153:Blotting, Western; D003882:Dermatomyositis / Q000473:pathology; D016650:Fluorescein-5-isothiocyanate; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017285:Polymyositis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
D005456:Fluorescent Dyes; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta; D016650:Fluorescein-5-isothiocyanate