Up-regulation of indoleamine 2,3-dioxygenase by lipopolysaccharide is regulated through activation of p38 mitogen-activated protein kinase and nuclear factor-κB

Indoleamine 2,3-dioxygenase (IDO) is up-regulated by interferon-γ (IFN-γ)-dependent and/or -independent mechanisms. IFN-γ-dependent mechanism is regulated through signal transducer and activator of transcription 1α (STAT1α) and interferon regulatory factor 1 (IRF-1). On the other hand, IFN-γ-independent mechanism of IDO induction has not been identified. In this study, we explored whether IDO induction by LPS requires the STAT1α and IRF-1 signaling pathways. IDO was induced by LPS or IFN-γ in THP-1 cells and a synergistic IDO induction occurred in THP-1 cultured with a combination of tumor necrosis factor-α, interleukin-6 and 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 results suggest that IDO induction by LPS is not regulated through the STAT1α or IRF-1 binding activities that are induced by IFN-γ, and may be related to the activity of the p38 MAPK pathway and/or NF-κB.