The Signal Transducer and Activator of Transcription 1α and Interferon Regulatory Factor 1 Are Not Essential for the Induction of Indoleamine 2,3-Dioxygenase by Lipopolysaccharide: Involvement of p38 Mitogen-Activated Protein Kinase and Nuclear Factor-κB Pathways, and Synergistic Effect of Several Proinflammatory Cytokines

Abstract

Indoleamine 2,3-dioxygenase (IDO) is induced by interferon (IFN)-gamma-mediated effects of the signal transducer and activator of transcription 1alpha (STAT1alpha) and interferon regulatory factor (IRF)-1. The induction of IDO can also be mediated through an IFN-gamma-independent mechanism, although the mechanism of induction has not been identified. In this study, we explored whether lipopolysaccharide (LPS) or several proinflammatory cytokines can induce IDO via an IFN-gamma-independent mechanism, and whether IDO induction by LPS requires the STAT1alpha and IRF-1 signaling pathways. IDO was induced by LPS or IFN-gamma in peripheral blood mononuclear cells and THP-1 cells, and a synergistic IDO induction occurred when THP-1 cells were cultured in the presence of a combination of tumor necrosis factor-alpha, interleukin-6 or interleukin-1beta. An electrophoretic mobility shift assay using STAT1alpha and IRF-1 consensus oligonucleotide probes showed no STAT1alpha or IRF-1 binding activities in LPS-stimulated THP-1 cells. Further, the LPS-induced IDO activity was inhibited by both p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) inhibitors. These findings suggest that the induction of IDO by LPS in THP-1 cells is not regulated by IFN-gamma via recruitment of STAT1alpha or IRF-1 to the intracellular signaling pathway, and may be related to the activity of the p38 MAPK pathway and NF-kappaB.

Inoculation of Bacillus Calmette-Guerin to mice induces an acute episode of sickness behavior followed by chronic depressive-like behavior

“…Similarly, plasma levels of IL-6, another cytokine involved in regulating sickness behavior, were elevated in BCGtreated mice 1 week after treatment, but drastically decreased thereafter. Chronic induction of depressive-like behavior by BCG was accompanied by sustained increase of plasma concentrations of TNF-α and IFN-γ, the two major cytokines that are responsible for IDO activation (Fujigaki et al, 2006;Takikawa et al, 1999). Although not directly tested in the present set of experiments, this last increase in plasma levels of TNF-α and IFN-γ probably explains the prolonged stimulation of lung IDO activity measured over the same period of time, as indicated by the positive correlation between IDO activity and the plasma levels of these cytokines.…”

“…Since KYN is the major product of TRP degradation (Dale et al, 2000), these results can be explained by an enhanced activation of the TRP-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) (Wirleitner et al, 2003). This extrahepatic enzyme is activated in monocytes, macrophages and brain microglia in response to proinflammatory cytokines, mainly interferon-gamma (IFN-γ) and tumor necrosis factoralpha (TNF-α) (Fujigaki et al, 2006;Takikawa et al, 1999). In cancer patients treated by cytokine immunotherapy, the fall in plasma levels of TRP is correlated with the intensity of depressive symptoms (Capuron et al, 2002b), indicating that IDO activation might play a role in cytokine-induced depressive symptoms (Dantzer et al, 2008).…”

IDO expression in the brain: a double-edged sword

“…While in most investigated in vitro models, IFN-γ is the main inducer of IDO in macrophages, DC, fibroblasts, and microglia [2][3][4][5]46], its expression can also be triggered by lipopolysaccharide (LPS) through an IFN-γ-independent mechanism [47]. The induction of IDO expression without IFN-γ signaling is not dependent on signal transducer and activator of transcription 1α and interferon regulatory factor-1 but requires p38 mitogen-activated protein kinase and nuclear factor-κB [48]. Thus, IDO induction is not restricted to Th1 cells secreting INF-γ but alternate triggers involving IL-10 and LPS.…”

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

“…This enzyme is induced by proinflammatory cytokines, mainly interferon-g (IFN-g) 5 and tumor-necrosis factor-a (TNF-a). 6,7 When IDO is activated in conditions of chronic inflammation, its degree of activation is correlated to the intensity of depressive symptoms, as observed in cancer patients chronically treated with IFN-a. 8 Acute activation of the peripheral innate immune system in laboratory animals, through the administration of the cytokine inducer lipopolysaccharide (LPS), induces depressive-like behavior, as measured by increased immobility in the forced-swim test (FST) and tail suspension test (TST), decreased consumption of a sweetened solution and a suppression of sexual behavior, 9,10 which can be attenuated by chronic antidepressant administration.…”