Glycogen synthase kinase-3β is critical for Interferon-α-induced serotonin uptake in human Jurkat T cells

Chiung Wen Tsao, Chiou Feng Lin, Hung Tsung Wu, Ching Ting Ma, Wei Ching Huang, Chia Yuan Hsieh, Pui Ching Choi, Kung Chia Young

Research output: Contribution to journalArticle

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Abstract

Dysregulation of glycogen synthase kinase (GSK)-3β contributes to the pathophysiology of mood disorders. However, how its regulation is responsible for the functioning of serotonin (5-HT) requires further investigation. Although enhancement of T-cell function may present an alternative strategy to treat depression, the precise mechanisms have yet to be established. Our previous studies have found that interferon-alpha (IFN-α) up-regulates serotonin transporter (5-HTT) expression and induces 5-HT uptake in T cells. The present study is to examine GSK-3β regulation on IFN-α-induced 5-HTT functions. GSK-3β short hairpin RNAs (shRNAs) or GSK-3β inhibitors decreased IFN-α-induced 5-HT uptake and 5-HTT expression. Src activation and calcium/calcium-activated calmodulin kinase II (CaMKII) were involved in IFN-α-induced phosphorylation of proline-rich tyrosine kinase 2 (Pyk2) (Tyr402) and GSK-3β (Tyr216), which regulated 5-HT uptake. GSK-3β knockdown blocked the IFN-α-induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 (Thr202/Tyr204) and signal transducer and transactivator (STAT) 1. In addition to inhibiting ERK, a selective 5-HTT inhibitor fluoxetine blocked IFN-α-induced activations of Src, CaMKII-regulated Pyk2/GSK-3β cascade, as well as STAT1 activation and translocation. These results indicated that calcium/CaMKII- and Src-regulated Pyk2 participated in IFN-α-induced GSK-3β activation and GSK-3β-regulated 5-HT uptake. GSK-3β signaling facilitated IFN-α-activated STAT1 by regulating ERK1/2, which controlled 5-HT uptake. Fluoxetine interfered with the Pyk2/GSK-3β cascade, thereby inhibiting IFN-α-induced 5-HT uptake.

Original languageEnglish
Pages (from-to)2556-2566
Number of pages11
JournalJournal of Cellular Physiology
Volume227
Issue number6
DOIs
Publication statusPublished - Jun 2012
Externally publishedYes

Fingerprint

Glycogen Synthase Kinase 3
Jurkat Cells
T-cells
Interferons
Serotonin
Interferon-alpha
T-Lymphocytes
Focal Adhesion Kinase 2
Calcium-Calmodulin-Dependent Protein Kinases
Chemical activation
Phosphorylation
Fluoxetine
Calcium
Serotonin Plasma Membrane Transport Proteins
Trans-Activators
Mitogen-Activated Protein Kinase 3
src-Family Kinases
Mitogen-Activated Protein Kinase 1
Extracellular Signal-Regulated MAP Kinases
Transducers

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Glycogen synthase kinase-3β is critical for Interferon-α-induced serotonin uptake in human Jurkat T cells. / Tsao, Chiung Wen; Lin, Chiou Feng; Wu, Hung Tsung; Ma, Ching Ting; Huang, Wei Ching; Hsieh, Chia Yuan; Choi, Pui Ching; Young, Kung Chia.

In: Journal of Cellular Physiology, Vol. 227, No. 6, 06.2012, p. 2556-2566.

Research output: Contribution to journalArticle

Tsao, Chiung Wen ; Lin, Chiou Feng ; Wu, Hung Tsung ; Ma, Ching Ting ; Huang, Wei Ching ; Hsieh, Chia Yuan ; Choi, Pui Ching ; Young, Kung Chia. / Glycogen synthase kinase-3β is critical for Interferon-α-induced serotonin uptake in human Jurkat T cells. In: Journal of Cellular Physiology. 2012 ; Vol. 227, No. 6. pp. 2556-2566.
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