Inhibition of Jun N-terminal kinase (JNK) enhances glucocorticoid receptor-mediated function in mouse hippocampal HT22 cells.
Mitogen-activated protein kinases (MAPKs), including Jun N-terminal kinase (JNK), promote inflammatory and proliferative responses to infection and other environmental stimuli including stress. Relevant to negative regulation of inflammatory pathways by glucocorticoids and the development of glucocorticoid resistance (observed in inflammatory disorders as well as certain neuropsychiatric disorders such as major depression), activation of JNK has been reported to inhibit glucocorticoid receptor (GR) function. In this study, the role of JNK pathways in modulating GR function was further investigated. Treatment of mouse hippocampal (HT22) cells with the selective JNK inhibitor, SP-600125 (0.1-10 microM), resulted in dose-dependent induction of GR-mediated MMTV-luciferase activity. SP-600125 also significantly enhanced dexamethasone-induced MMTV-luciferase activity, while increasing GR binding to the glucocorticoid responsive element, both in the presence and absence of Dex. Similar effects were observed in mouse fibroblast cells (LMCAT), and in HT22 cells treated with a JNK specific antisense oligonucleotide. The induction of GR-mediated function by SP-600125 was not due to altered cytosolic GR binding or GR protein expression or enhancement of GR nuclear translocation as determined by Western blot. Taken together, the data indicate that constitutive expression of JNK plays a tonic inhibitory role in GR function, which is consistent with findings that activation of JNK pathways inhibits GR. The data also identify potential pathways involved in the pathogenesis of the glucocorticoid resistance found in certain chronic immune/inflammatory diseases and subgroups of patients with major depression. Moreover, JNK pathways may represent a therapeutic target for normalization of GR function in these disorders.
Wang
Xiaohong
X
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.
Wu
Huixia
H
Lakdawala
Viraj S
VS
Hu
Fang
F
Hanson
Nicola D
ND
Miller
Andrew H
AH
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D017930:Genes, Reporter; D006624:Hippocampus / Q000187:drug effects*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008156:Luciferases / Q000235:genetics; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000235:genetics; D014162:Transfection
D000873:Anthracenes; D004791:Enzyme Inhibitors; D016376:Oligonucleotides, Antisense; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; C432165:pyrazolanthrone; D003907:Dexamethasone; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases