title: Altered glucocorticoid receptor signaling cascade in lymphocytes of bipolar disorder patients.
abstract: Bipolar disorder (BD) is characterized by hypothalamic pituitary adrenal (HPA) axis hyperactivity, glucocorticoid insensitivity and alterations in serotonin and inflammatory mediators. The glucocorticoid receptor (GR), activator protein-1 (AP-1), nuclear factor-kappa B (NF-kappaB) and c-jun N-terminal kinase (JNK) regulate the above mentioned processes; we therefore assessed their role in BD. Fifteen bipolar depressed patients under multiple anti-depressant therapy, 15 bipolar euthymics under lithium monotherapy and 25 matched controls were studied. Whole cell and nuclear extracts from lymphocytes were immunoblotted for GR, c-fos, JNK and NF-kappaB and nuclear aliquots were submitted to electrophoretic mobility shift assay for GR, AP-1 and NF-kappaB. Associations with the anti-depressant therapy and the state of the disease were also sought. Results, expressed as percentage of pooled protein standard sample intergraded optical density (IOD) (mean +/- SD), revealed: (a) depressed patients had significantly higher GR levels than controls in whole cell (82.63 +/- 6.18 versus 76.27 +/- 4.21%, P < 0.01) and nuclear extracts (86.66 +/- 3.81 versus 81.72 +/- 2.71%, P < 0.001) but lower GR-DNA binding (68.75 +/- 7.91 versus 81.84 +/- 4.25%, P < 0.05). Euthymics had normalized whole cell GR content (73.64 +/- 5.95%) and GR-DNA binding activity (76.82 +/- 7.29%) but higher nuclear GR content (86.89+/-3.96%, P<0.01) than controls; (b) nuclear c-fos content and AP-1-DNA-binding were significantly lower in depressed patients than controls (80.49 +/- 2.03 versus 84.82 +/- 3.48%, P < 0.05 and 78.46 +/- 4.17 versus 84.80 +/- 5.79%, P < 0.05, respectively). Euthymics however, showed similar nuclear c-fos and AP-1-DNA-binding to controls (85.48 +/- 2.71 and 87.78 +/- 3.54%, respectively) but lower whole cell c-fos than in controls (81.18 +/- 3.87 versus 87.01 +/- 4.22%, P < 0.001); (c) depressed patients had significantly lower whole cell and nuclear JNK than controls (67.01 +/- 4.29 versus 72.00 +/- 3.68%, P < 0.05 and 80.10 +/- 2.53 versus 86.96 +/- 2.49%, P < 0.001) whereas euthymics showed lower nuclear JNK (83.27 +/- 1.93%, P < 0.01); (d) whole cell NF-kB was higher in the depressed patients than in controls (67.30 +/- 5.00 versus 63.63 +/- 3.3%, P < 0.05). Concluding, intracellular signaling of GR, AP-1 and JNK are altered in BD and may underly disease aetiopathogenesis and/or reflect the effect of the anti-depressants.
authors.affiliation: Laboratory of Biological Chemistry, Medical School, University of Athens, 75 Mikras Asias street, Goudi, GR 11527 Athens, Attiki, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Spiliotaki
authors.forename: V
authors.initials: V
authors.lastname: Salpeas
authors.forename: P
authors.initials: P
authors.lastname: Malitas
authors.forename: V
authors.initials: V
authors.lastname: Alevizos
authors.forename: P
authors.initials: P
authors.lastname: Moutsatsou
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000928:Antidepressive Agents / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D003863:Depression / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D016555:Matched-Pair Analysis; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012016:Reference Values; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018709:Statistics, Nonparametric; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases