Aryl hydrocarbon receptor in combination with STAT1 regulates LPS-induced inflammatory responses

Abstract

ARTICLE The Rockefeller University Press $30.00 J. Exp. Med. Vol. 206 No. 9 2027-2035 www.jem.org/cgi/doi/10.1084/jem.20090560 2027 APCs such as macrophages are important for in- nate immune defense and for the generation and regulation of adaptive immunity against various pathogens. Activated macrophages produce pro- inflammatory cytokines, including IL-6, IL-12, and TNF-, which activate T cells and induce their differentiation. It has been demonstrated that IL-6 combined with TGF- participates in the differentiation of naive T cells into IL-17– producing T helper (Th17) cells (Bettelli et al., 2006). More recently, our group and others demonstrated that Aryl hydrocarbon receptor (Ahr), also known as dioxin receptor, is induced by TGF- plus IL-6 in naive T cells and partici- pates in the differentiation of Th17 cells (Kimura et al., 2008; Quintana et al., 2008; Veldhoen et al., 2008). We proved that Ahr participates in Th17 cell development through regulating acti- vation of signal-transducer-and-activator-of- transcription 1 (Stat1), which suppresses Th17 cell differentiation (Stumhofer et al. 2006; Kimura et al., 2008). Ahr is a ligand-activated transcription fac- tor that belongs to the basic-helix-loop-helix- PER-ARNT-SIM family (Burbach et al., 1992; Ema et al., 1992; Fujii-Kuriyama et al., 1994). Upon binding with a ligand, Ahr un- dergoes a conformation change, translocates to the nucleus, and dimerizes with the Ahr nu- clear translocator (Arnt). Within the nucleus, the Ahr/Arnt heterodimer binds to a specific sequence, designated a xenobiotic responsive element, which causes a variety of toxicologi- cal effects (Dragan and Schrenk, 2000; Ohtake et al., 2003; Puga et al., 2005). In immune CORRESPONDENCE Tadamitsu Kishimoto: kishimot@ imed3.med.osaka-u.ac.jp Abbreviations used: Ahr, aryl hydrocarbon receptor; ChIP, chromatin immunoprecipita- tion; IMDM, Iscove’s modified Dulbecco’s medium; MyD88, myeloid differentiation factor 88; ODN, oligodeoxynucleo- ti

Key Biomarkers