Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses.
Toll-like receptor (TLR) signals perform a crucial role in innate immune responses to pathogens. In this study, we found that the aryl hydrocarbon receptor (Ahr) negatively regulates inflammatory responses mediated by lipopolysaccharide (LPS) in macrophages. Ahr was induced in macrophages stimulated by LPS, but not by transforming growth factor (TGF)-beta plus interleukin (IL)-6, which can induce Ahr in naive T cells. The production of IL-6 and tumor necrosis factor (TNF)-alpha by LPS was significantly elevated in Ahr-deficient macrophages compared with that in wild-type (WT) cells. Ahr-deficient mice were more highly sensitive to LPS-induced lethal shock than WT mice. Signal transducer and activator of transcription 1 (Stat1) deficiency, as well as Ahr deficiency, augmented LPS-induced IL-6 production. We found that Ahr forms a complex with Stat1 and nuclear factor-kappa B (NF-kappaB) in macrophages stimulated by LPS, which leads to inhibition of the promoter activity of IL-6. Ahr thus plays an essential role in the negative regulation of the LPS signaling pathway through interaction with Stat1.
Kimura
Akihiro
A
Laboratory of Immune Regulation, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka 565-0871, Japan.
Naka
Tetsuji
T
Nakahama
Taisuke
T
Chinen
Ichino
I
Masuda
Kazuya
K
Nohara
Keiko
K
Fujii-Kuriyama
Yoshiaki
Y
Kishimoto
Tadamitsu
T
D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000276:immunology*; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides; D008156:Luciferases; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000276:immunology* / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D017931:DNA Primers; D015850:Interleukin-6; D008070:Lipopolysaccharides; D046912:Multiprotein Complexes; D016328:NF-kappa B; D018336:Receptors, Aryl Hydrocarbon; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases
Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8185-9
1325649
Mol Cell Endocrinol. 2008 Sep 10;291(1-2):87-94
18565642
J Exp Med. 2003 Jan 20;197(2):263-8
12538665
J Exp Med. 2003 Oct 6;198(7):1043-55
14517278
Nat Immunol. 2006 Sep;7(9):937-45
16906166
Nature. 2003 May 29;423(6939):545-50
12774124
J Biol Chem. 1999 Jan 1;274(1):510-5
9867872
Nature. 2008 May 1;453(7191):106-9
18362914
J Immunol. 2005 Oct 1;175(7):4184-8
16177056
Nat Rev Immunol. 2003 Feb;3(2):169-76
12563300
Food Addit Contam. 2000 Apr;17(4):289-302
10912243
Biochem Pharmacol. 2005 Jan 15;69(2):199-207
15627472
J Biol Chem. 2000 Jan 28;275(4):2943-50
10644764
Nature. 2006 May 11;441(7090):235-8
16648838
Nature. 2007 Mar 29;446(7135):562-6
17392787
Nat Immunol. 2002 Apr;3(4):392-8
11896392
Nature. 2008 May 1;453(7191):65-71
18362915
Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9721-6
18607004
Exp Clin Immunogenet. 1994;11(2-3):65-74
7826667
Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17089-94
16287972
J Immunol. 2005 Dec 1;175(11):7348-56
16301641
Nature. 2004 Jul 8;430(6996):218-22
15241416
J Immunol. 1997 Aug 1;159(3):1412-7
9233638
J Exp Med. 2009 Jan 16;206(1):43-9
19114668
Mol Endocrinol. 2007 Dec;21(12):2941-55
17823304
Annu Rev Immunol. 2001;19:683-765
11244051
Chem Biol Interact. 2002 Sep 20;141(1-2):97-115
12213387
Nat Rev Immunol. 2004 Jul;4(7):499-511
15229469
Nat Immunol. 2003 May;4(5):471-7
12679810
Biochem Biophys Res Commun. 1992 Apr 15;184(1):246-53
1314586
J Biol Chem. 2005 Feb 18;280(7):5491-5
15623538
Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2532-6
8460169
Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):779-82
10639156
Cancer Res. 2001 Aug 15;61(16):6120-30
11507062
Immunity. 1999 Jul;11(1):115-22
10435584
Immunity. 2002 Nov;17(5):677-87
12433373
Nat Rev Immunol. 2007 Jun;7(6):454-65
17525754