Molecular Determinants of Crosstalk Between Nuclear Receptors and Toll-like Receptors

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2005 Sep 7

PMID 16143103

Citations 267

Authors

Sumito Ogawa

Jean Lozach

Chris Benner

Gabriel Pascual

Rajendra K Tangirala

Stefan Westin

Alexander Hoffmann

Shankar Subramaniam

Michael David

Michael G Rosenfeld

Christopher K Glass

Affiliations

Soon will be listed here.

Abstract

Nuclear receptors (NRs) repress transcriptional responses to diverse signaling pathways as an essential aspect of their biological activities, but mechanisms determining the specificity and functional consequences of transrepression remain poorly understood. Here, we report signal- and gene-specific repression of transcriptional responses initiated by engagement of toll-like receptors (TLR) 3, 4, and 9 in macrophages. The glucocorticoid receptor (GR) represses a large set of functionally related inflammatory response genes by disrupting p65/interferon regulatory factor (IRF) complexes required for TLR4- or TLR9-dependent, but not TLR3-dependent, transcriptional activation. This mechanism requires signaling through MyD88 and enables the GR to differentially regulate pathogen-specific programs of gene expression. PPARgamma and LXRs repress overlapping transcriptional targets by p65/IRF3-independent mechanisms and cooperate with the GR to synergistically transrepress distinct subsets of TLR-responsive genes. These findings reveal combinatorial control of homeostasis and immune responses by nuclear receptors and suggest new approaches for treatment of inflammatory diseases.

Citing Articles

Insights into IAV Replication and Lipid Metabolism in Suspension-Adapted MDCK-STAT1-KO Cells.

Ye Q, Yao H, Xiao Z, Zhao L, Tan W Vaccines (Basel). 2025; 13(2).

PMID: 40006653 PMC: 11860519. DOI: 10.3390/vaccines13020106.

Lipidome disruption in Alzheimer's disease brain: detection, pathological mechanisms, and therapeutic implications.

He S, Xu Z, Han X Mol Neurodegener. 2025; 20(1):11.

PMID: 39871348 PMC: 11773937. DOI: 10.1186/s13024-025-00803-6.

PPAR agonists for the treatment of cholestatic liver diseases: Over a decade of clinical progress.

Hayes C, Gallucci G, Boyer J, Assis D, Ghonem N Hepatol Commun. 2024; 9(1).

PMID: 39699308 PMC: 11661771. DOI: 10.1097/HC9.0000000000000612.

Oxysterol binding protein regulates the resolution of TLR-induced cytokine production in macrophages.

Diercks A, Podolskaia I, Murray T, Jahn A, Mai D, Liu D Proc Natl Acad Sci U S A. 2024; 121(33):e2406492121.

PMID: 39361877 PMC: 11331125. DOI: 10.1073/pnas.2406492121.

The Glucocorticoid Receptor: Isoforms, Functions, and Contribution to Glucocorticoid Sensitivity.

Lockett J, Inder W, Clifton V Endocr Rev. 2024; 45(4):593-624.

PMID: 38551091 PMC: 11244253. DOI: 10.1210/endrev/bnae008.

References

Ogawa S, Fujita M, Ishii Y, Tsurukami H, Hirabayashi M, Ikeda K . Impaired estrogen sensitivity in bone by inhibiting both estrogen receptor alpha and beta pathways. J Biol Chem. 2000; 275(28):21372-9. DOI: 10.1074/jbc.M909675199. View

Nissen R, Yamamoto K . The glucocorticoid receptor inhibits NFkappaB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes Dev. 2000; 14(18):2314-29. PMC: 316928. DOI: 10.1101/gad.827900. View

Sato M, Suemori H, Hata N, Asagiri M, Ogasawara K, Nakao K . Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction. Immunity. 2000; 13(4):539-48. DOI: 10.1016/s1074-7613(00)00053-4. View

Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H . A Toll-like receptor recognizes bacterial DNA. Nature. 2000; 408(6813):740-5. DOI: 10.1038/35047123. View

Hacker H, Vabulas R, Takeuchi O, Hoshino K, Akira S, Wagner H . Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6. J Exp Med. 2000; 192(4):595-600. PMC: 2193231. DOI: 10.1084/jem.192.4.595. View

Chawla A, Boisvert W, Lee C, Laffitte B, Barak Y, Joseph S . A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 2001; 7(1):161-71. DOI: 10.1016/s1097-2765(01)00164-2. View

. Creating the gene ontology resource: design and implementation. Genome Res. 2001; 11(8):1425-33. PMC: 311077. DOI: 10.1101/gr.180801. View

Nagpal S, Lu J, Boehm M . Vitamin D analogs: mechanism of action and therapeutic applications. Curr Med Chem. 2001; 8(13):1661-79. DOI: 10.2174/0929867013371950. View

Alexopoulou L, Holt A, Medzhitov R, Flavell R . Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001; 413(6857):732-8. DOI: 10.1038/35099560. View

10.

Rogatsky I, Zarember K, Yamamoto K . Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones. EMBO J. 2001; 20(21):6071-83. PMC: 125702. DOI: 10.1093/emboj/20.21.6071. View

11.

Kawai T, Takeuchi O, Fujita T, Inoue J, Muhlradt P, Sato S . Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol. 2001; 167(10):5887-94. DOI: 10.4049/jimmunol.167.10.5887. View

12.

Reichardt H, Tuckermann J, Gottlicher M, Vujic M, Weih F, Angel P . Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor. EMBO J. 2001; 20(24):7168-73. PMC: 125338. DOI: 10.1093/emboj/20.24.7168. View

13.

Janeway Jr C, Medzhitov R . Innate immune recognition. Annu Rev Immunol. 2002; 20:197-216. DOI: 10.1146/annurev.immunol.20.083001.084359. View

14.

Baek S, Ohgi K, Rose D, Koo E, Glass C, Rosenfeld M . Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein. Cell. 2002; 110(1):55-67. DOI: 10.1016/s0092-8674(02)00809-7. View

15.

Yamamoto M, Sato S, Mori K, Hoshino K, Takeuchi O, Takeda K . Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol. 2002; 169(12):6668-72. DOI: 10.4049/jimmunol.169.12.6668. View

16.

Sasik R, Calvo E, Corbeil J . Statistical analysis of high-density oligonucleotide arrays: a multiplicative noise model. Bioinformatics. 2002; 18(12):1633-40. DOI: 10.1093/bioinformatics/18.12.1633. View

17.

Joseph S, Castrillo A, Laffitte B, Mangelsdorf D, Tontonoz P . Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med. 2003; 9(2):213-9. DOI: 10.1038/nm820. View

18.

Welch J, Ricote M, Akiyama T, Gonzalez F, Glass C . PPARgamma and PPARdelta negatively regulate specific subsets of lipopolysaccharide and IFN-gamma target genes in macrophages. Proc Natl Acad Sci U S A. 2003; 100(11):6712-7. PMC: 164512. DOI: 10.1073/pnas.1031789100. View

19.

Halees A, Leyfer D, Weng Z . PromoSer: A large-scale mammalian promoter and transcription start site identification service. Nucleic Acids Res. 2003; 31(13):3554-9. PMC: 168956. DOI: 10.1093/nar/gkg549. View

20.

Vallejo J, Mann D . Antiinflammatory therapy in myocarditis. Curr Opin Cardiol. 2003; 18(3):189-93. DOI: 10.1097/00001573-200305000-00003. View