title: The signal transducer and activator of transcription 1alpha 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-kappaB 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.
authors: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194.
authors: Hidetsugu
authors: H
authors: Fujigaki
authors: Kuniaki
authors: K
authors: Saito
authors: Suwako
authors: S
authors: Fujigaki
authors: Masao
authors: M
authors: Takemura
authors: Kaori
authors: K
authors: Sudo
authors: Hiroshi
authors: H
authors: Ishiguro
authors: Mitsuru
authors: M
authors: Seishima