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

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.

Molecular Biology of Atherosclerosis

“…PYK2 activates GSK-3␤ by tyrosine phosphorylation (1813). Additionally, the PYK2-Src complex can apparently activate ADAM17 with release of HB-EGF and transactivation of EGFR signaling, providing an additional source of PI3K and Grb2-Sos-Ras activation (616,617) and a sustained release of ROS (805).…”

Fluoxetine a novel anti-hepatitis C virus agent via ROS-, JNK-, and PPARβ/γ-dependent pathways

“…Fluoxetine enhanced IFN-a-activated STAT-1 signals under HCV infection status, whereas it did not affect this activation in Huh7.5 (Fig. 3) and Jurkat T cells (Tsao et al, 2012).…”

“…SSRI alters hepatic lipid biosynthesis (McIntyre et al, 2010), has an anti-inflammatory property (Tynan et al, 2012), and affects negatively MAPK or STAT-1 signals (Tsao et al, 2012). Moreover, SSRI acts as a suppressor to infectivity and replication of human immunodeficiency virus (HIV) (Benton et al, 2010) and is a potent inhibitor of enterovirus replication (Ulferts et al, 2013;Zuo et al, 2012); however, it is not clear whether the presence of SSRI can affect anti-HCV treatment.…”

Isoorientin Inhibits Inflammation in Macrophages and Endotoxemia Mice by Regulating Glycogen Synthase Kinase 3β

“…The MAPK signaling pathway regulates oxidative stress and injury response in cells. GSK3β knockdown blocks the IFN-α-induced phosphorylation of extracellular signalregulated kinase (ERK) 1/2 (Thr202/Tyr204) in human Jurkat T cells [24].…”

“…Phosphorylation of GSK3β at the Ser9 site inactivates GSK3β [20][21][22]. GSK3β regulates its downstream signal molecules such as NF-κB, ERK, Nrf2, and HO-1 in several or animal models [23][24][25].…”