The Signal Transducer and Activator of Transcription 1a 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-jB

Indoleamine 2,3-dioxygenase (IDO) is induced by interferon (IFN)-c–mediated effects of the signal transducer and activator of transcription 1a (STAT1a) and interferon regulatory factor (IRF)-1. The induction of IDO can also be mediated through an IFN-c–independent mechanism, although the mechanism of induction has not been identified. In this study, we explored whether lipopolysaccharide (LPS) or several pro-inflammatory cytokines can induce IDO via an IFN-c–independent mechanism, and whether IDO induction by LPS requires the STAT1a and IRF-1 signaling pathways. IDO was induced by LPS or IFN-c 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-a, interleukin-6 or interleukin-1b. An electrophoretic mobility shift assay using STAT1a and IRF-1 consensus oligonucleotide probes showed no STAT1a 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-jB (NF-jB) inhibitors. These findings suggest that the induction of IDObyLPS inTHP-1 cells is not regulated by IFN-c via recruitmen