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

• Published in: Journal of biochemistry (Tokyo) Vol. 139; no. 4; pp. 655 - 662
• Main Authors: Fujigaki, Hidetsugu, Saito, Kuniaki, Fujigaki, Suwako, Takemura, Masao, Sudo, Kaori, Ishiguro, Hiroshi, Seishima, Mitsuru
• Format: Journal Article
• Language: English
• Published: Oxford University Press 01.04.2006
• Subjects: 3-dioxygenase; antibody; electrophoretic mobility shift assay; EMSA; enzyme induction; GAS; IDO; IFN; IFN-γ–activated site; indoleamine 2; interferon; interferon regulatory factor; interferon regulatory factor-1; interferon-stimulated response elements; interleukin; IRF; ISRE; L-KYN; L-Kynurenine; lipopolysaccharide; LPS; MAPK; mitogen-activated protein kinase; NF-κB; nuclear factor-κB; PBMC; peripheral blood mononuclear cells; signal transducer and activator of transcription 1α; STAT1α; TNF; Trp; tryptophan; tumor necrosis factor
• ISSN: 0021-924X; 1756-2651
• DOI: 10.1093/jb/mvj072

Indoleamine 2,3-dioxygenase (IDO) is induced by interferon (IFN)-γ-mediated effects of the signal transducer and activator of transcription 1α (STAT1α) and interferon regulatory factor (IRF)-1. The induction of IDO can also be mediated through an IFN-γ-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-γ-independent mechanism, and whether IDO induction by LPS requires the STAT1α and IRF-1 signaling pathways. IDO was induced by LPS or IFN-γ 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-α, interleukin-6 or interleukin-1β. An electrophoretic mobility shift assay using STAT1α and IRF-1 consensus oligonucleotide probes showed no STAT1α 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-κB (NF-κB) inhibitors. These findings suggest that the induction of IDO by LPS in THP-1 cells is not regulated by IFN-γ via recruitment of STAT1α or IRF-1 to the intracellular signaling pathway, and may be related to the activity of the p38 MAPK pathway and NF-κB.