Patients with multiple sclerosis resisted to glucocorticoid therapy: abnormal expression of heat-shock protein 90 in glucocorticoid receptor complex.
OBJECTIVE
The majority of patients with multiple sclerosis (MS) respond favorably to glucocorticoids (GS) for their relapse treatment (steroid-sensitive multiple sclerosis). Unfortunately, a small subset of patients with multiple-sclerosis fails to adequately respond even to high dose of GS (steroid-resistant multiple sclerosis). Mechanism of GS therapeutic unresponsiveness is not resolved.


METHODS
Transcripts for glucocorticoid receptor (GR) was assessed in peripheral blood mononuclear cells by real-time polymerase chain reaction in patients with steroid-sensitive and steroid-resistant multiple sclerosis. GR expression was assessed by Western blotting. The amount of heat-shock protein 90 (hsp90) in GR cytoplasmic complex was assessed by immunoprecipitation. Hsp90 was shown to stabilize the GR complex, to prevent its translocation to nucleus, and to inhibit GR transcription.


RESULTS
Peripheral blood mononuclear cells of steroid-resistant multiple sclerosis transcripts for all three isoforms of GR, alpha, beta, and gamma, were reduced by about two-folds compared with patients with steroid-sensitive multiple sclerosis. We have not found an increase in the beta and gamma transcripts of GR, which might serve as a dominant negative mutants, over GR alpha in steroid-resistant multiple sclerosis. The amount of hsp90 in the GR complex in cytoplasm was significantly higher in steroid-resistant multiple sclerosis compared with steroid-sensitive multiple sclerosis.


CONCLUSIONS
Molecular mechanism of GS unresponsiveness in some patients with multiple sclerosis might be related to increased presence of hsp90 in the GR cytoplasmic complex, leading to the inhibition of GR translocation to nucleus and reduction in its transcription.
Department of Neurology, Medical University of Lodz, Lodz, Poland.
M
M
Matysiak
B
B
Makosa
A
A
Walczak
K
K
Selmaj
D000328:Adult; D002455:Cell Division / Q000187:drug effects; D003907:Dexamethasone / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000627:therapeutic use*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000235:genetics*
C497471:GRgamma protein, human; D005938:Glucocorticoids; D018841:HSP90 Heat-Shock Proteins; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta; D003907:Dexamethasone