Interferon-alpha-induced modulation of glucocorticoid and serotonin receptors as a mechanism of depression.
OBJECTIVE
The mechanism of interferon (IFN)-alpha-induced depression remains poorly understood. Recently, modulation of glucocorticoid receptor (GR) and serotonin receptor 1A (5-HTR1A) were implicated in mechanism(s) leading to depression. To gain insight into this mechanism, we assessed the effect of IFN-alpha on the modulation of GR and 5-HTR1A expression.


METHODS
Hepatoblastoma, myelocyte-derived and T cell leukemia-derived cell lines were treated with titrated doses of IFN-alpha for different incubation times and analyzed by Western blot, RT-PCR, and microarrays. Dose- and time-dependent decreases of proteins and mRNA levels of GR and 5-HTR1A were observed.


RESULTS
The expression of GR and 5-HTR1A in cells treated for 6 days decreased by 74 and 72%, respectively. Recovery was observed following IFN-alpha withdrawal. Co-incubation with tricyclic antidepressants (desipramine) or serotonin reuptake inhibitors (fluoxetine) attenuated the effect of IFN-alpha on GR or 5-HTR1A. GR and 5-HTR1A were unaffected by treatment with either IFN-gamma or tauroursodeoxycholic acid (TUDCA). However, the effect of IFN-alpha on GR was abolished when used in combination with TUDCA.


CONCLUSIONS
In conclusion, IFN-alpha downregulated GR and 5-HTR1A levels in cell lines. These levels of GR and 5-HTR1A, following IFN-alpha-induced downregulation, recovered after withdrawal of IFN-alpha or addition of desipramine or fluoxetine. These data provide insights regarding pathogenesis of IFN-alpha-induced depression.
Cai
Wei
W
Department of Medicine, Veterans Affairs Medical Center (151B), 2002 Holcombe Blvd., Houston, TX 77030, USA.
Khaoustov
Vladimir I
VI
Xie
Qing
Q
Pan
Tianhong
T
Le
Weidong
W
Yoffe
Boris
B
D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D003865:Major Depressive Disorder / Q000139:chemically induced*; D003891:Desipramine / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D018197:Hepatoblastoma; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D019169:Jurkat Cells; D008113:Liver Neoplasms; D020411:Oligonucleotide Array Sequence Analysis; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology
D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D000998:Antiviral Agents; D016898:Interferon-alpha; D011965:Receptors, Glucocorticoid; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D003891:Desipramine