© 2006 The Japanese Biochemical Society.
Regular Paper |
The Signal Transducer and Activator of Transcription 1
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-
B Pathways, and Synergistic Effect of Several Proinflammatory Cytokines
1 Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194; 2 Laboratory of Neurotoxicology, National Institute of Mental Health, Building 10 Room 3D42, MSC 1262, 10 Center Drive, Bethesda, MD 20892, USA; and 3 Carna Biosciences Inc., KIBC 511, 5-5-2 Minatojima-Minamimachi, Chuoku, Kobe 650-0047
* To whom correspondence should be addressed. Tel: +81-58-230-6430, Fax: +81-58-230-6431, E-mail: saito{at}cc.gifu-u.ac.jp
Indoleamine 2,3-dioxygenase (IDO) is induced by interferon (IFN)-
–mediated effects of the signal transducer and activator of transcription 1
(STAT1) and interferon regulatory factor (IRF)-1. The induction of IDO can also be mediated through an IFN-–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-–independent mechanism, and whether IDO induction by LPS requires the STAT1 and IRF-1 signaling pathways. IDO was induced by LPS or IFN- 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-, interleukin-6 or interleukin-1ß. An electrophoretic mobility shift assay using STAT1 and IRF-1 consensus oligonucleotide probes showed no STAT1 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-
B (NF-B) inhibitors. These findings suggest that the induction of IDO by LPS in THP-1 cells is not regulated by IFN- via recruitment of STAT1 or IRF-1 to the intracellular signaling pathway, and may be related to the activity of the p38 MAPK pathway and NF-B.