The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index.
Reciprocal Negative Cross-Talk between Liver X Receptors (LXRs) and STAT1: Effects on IFN-γ–Induced Inflammatory Responses and LXR-Dependent Gene Expression
Abstract
Liver X receptors (LXRs) exert key functions in lipid homeostasis and in control of inflammation. In this study we have explored the impact of LXR activation on the macrophage response to the endogenous inflammatory cytokine IFN-γ. Transcriptional profiling studies demonstrate that ∼38% of the IFN-γ–induced transcriptional response is repressed by LXR activation in macrophages. LXRs also mediated inhibitory effects on selected IFN-γ–induced genes in primary microglia and in a model of IFN-γ–induced neuroinflammation in vivo. LXR activation resulted in reduced STAT1 recruitment to the promoters tested in this study without affecting STAT1 phosphorylation. A closer look into the mechanism revealed that SUMOylation of LXRs, but not the presence of nuclear receptor corepressor 1, was required for repression of the NO synthase 2 promoter. We have also analyzed whether IFN-γ signaling exerts reciprocal effects on LXR targets. Treatment with IFN-γ inhibited, in a STAT1-dependent manner, the LXR-dependent upregulation of selective targets, including ATP-binding cassette A1 (ABCA1) and sterol response element binding protein 1c. Downregulation of ABCA1 expression correlated with decreased cholesterol efflux to apolipoprotein A1 in macrophages stimulated with IFN-γ. The inhibitory effects of IFN-γ on LXR signaling did not involve reduced binding of LXR/retinoid X receptor heterodimers to target gene promoters. However, overexpression of the coactivator CREB-binding protein/p300 reduced the inhibitory actions of IFN-γ on the Abca1 promoter, suggesting that competition for CREB-binding protein may contribute to STAT1-dependent downregulation of LXR targets. The results from this study suggest an important level of bidirectional negative cross-talk between IFN-γ/STAT1 and LXRs with implications both in the control of IFN-γ–mediated immune responses and in the regulation of lipid metabolism.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“LXR activation modulates pro-inflammatory responses in animal models of atherosclerosis and neuroinflammation via inhibition of nuclear factor (NF)-κB and STAT-dependent gene transcription.51”
From Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist (2024) · cites this paper as [52]
Citations
Cites
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.211 · Cited by 35,890
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkn923 · Cited by 14,108
Heinz, S., Benner, C., Spann, N., Bertolino, E., Lin, Y. C., Laslo, P., Cheng, J. X., Murre, C., Singh, H., & Glass, C. K. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.05.004 · Cited by 13,382
The nuclear receptor superfamily: the second decade
Mangelsdorf, D. J., Thummel, C., Beato, M., Herrlich, P., Schütz, G., Umesono, K., Blumberg, B., Kastner, P., Mark, M., Chambon, P., et al. (1995) · Cell · doi:10.1016/0092-8674(95)90199-x · Cited by 6,964
The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation
Ricote, M., Li, A. C., Willson, T. M., Kelly, C. J., & Glass, C. K. (1998) · Nature · doi:10.1038/34178 · Cited by 3,525
Wen, Z., Zhong, Z., & Darnell, J. E. (1995) · Cell · doi:10.1016/0092-8674(95)90311-9 · Cited by 1,974
Repa, J. J., Liang, G., Ou, J., Bashmakov, Y. K., Lobaccaro, J. A., Shimomura, I., Shan, B., Brown, M. S., Goldstein, J. L., & Mangelsdorf, D. J. (2000) · Genes & Development · doi:10.1101/gad.844900 · Cited by 1,724
Peet, D. J., Turley, S. D., Ma, W., Janowski, B. A., Lobaccaro, J.-M. A., Hammer, R. E., & Mangelsdorf, D. J. (1998) · Cell · doi:10.1016/s0092-8674(00)81432-4 · Cited by 1,436
A PPARγ-LXR-ABCA1 Pathway in Macrophages Is Involved in Cholesterol Efflux and Atherogenesis
Chawla, A., Boisvert, W. A., Lee, C.-H., Laffitte, B. A., Barak, Y., Joseph, S. B., Liao, D., Nagy, L., Edwards, P. A., Curtiss, L. K., et al. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00164-2 · Cited by 1,347
Regulation of Absorption and ABC1-Mediated Efflux of Cholesterol by RXR Heterodimers
Repa, J. J., Turley, S. D., Lobaccaro, J.-M. A., Medina, J., Li, L., Lustig, K., Shan, B., Heyman, R. A., Dietschy, J. M., & Mangelsdorf, D. J. (2000) · Science · doi:10.1126/science.289.5484.1524 · Cited by 1,301
Reciprocal regulation of inflammation and lipid metabolism by liver X receptors
Joseph, S. B., Castrillo, A., Laffitte, B. A., Mangelsdorf, D. J., & Tontonoz, P. (2003) · Nature Medicine · doi:10.1038/nm820 · Cited by 1,158
THE IFNγ RECEPTOR:A Paradigm for Cytokine Receptor Signaling
Bach, E. A., Aguet, M., & Schreiber, R. D. (1997) · Annual Review of Immunology · doi:10.1146/annurev.immunol.15.1.563 · Cited by 1,050
Sterol-dependent Transactivation of theABC1 Promoter by the Liver X Receptor/Retinoid X Receptor
Costet, P., Luo, Y., Wang, N., & Tall, A. R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003337200 · Cited by 991
Liver X receptors as integrators of metabolic and inflammatory signaling
Zelcer, N. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27883 · Cited by 978
Structural requirements of ligands for the oxysterol liver X receptors LXRα and LXRβ
Janowski, B. A., Grogan, M. J., Jones, S. A., Wisely, G. B., Kliewer, S. A., Corey, E. J., & Mangelsdorf, D. J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.1.266 · Cited by 965
Creating the Gene Ontology Resource: Design and ImplementationPreprint
The Gene Ontology Consortium (2001) · Genome Research · doi:10.1101/gr.180801 · Cited by 957
ApoE Promotes the Proteolytic Degradation of Aβ
Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.010 · Cited by 876
LXR Regulates Cholesterol Uptake Through Idol-Dependent Ubiquitination of the LDL Receptor
Zelcer, N., Hong, C., Boyadjian, R., & Tontonoz, P. (2009) · Science · doi:10.1126/science.1168974 · Cited by 848
Creating the gene ontology resource: design and implementation.
Blake, J. A., Corradi, J., Eppig, J. T., Hill, D. P., Richardson, J. E., & Ringwald, M. (2001) · The Mouseion at the JAXlibrary (Jackson Laboratory) · Cited by 826
Liu, S.-Y., Aliyari, R., Chikere, K., Li, G., Marsden, M. D., Smith, J. K., Pernet, O., Guo, H., Nusbaum, R., Zack, J. A., et al. (2013) · Immunity · doi:10.1016/j.immuni.2012.11.005 · Cited by 678
Molecular determinants of crosstalk between nuclear receptors and toll-like receptors
Ogawa, S., Lozach, J., Benner, C., Pascual, G., Tangirala, R. K., Westin, S., Hoffmann, A., Subramaniam, S., David, M., Rosenfeld, M. G., et al. (2005) · Cell · doi:10.1016/j.cell.2005.06.029 · Cited by 647
Spann, N. J., Garmire, L. X., McDonald, J. G., Myers, D. S., Milne, S. B., Shibata, N., Reichart, D. R., Fox, J. N., Shaked, I., Heudobler, D., et al. (2012) · Cell · doi:10.1016/j.cell.2012.06.054 · Cited by 630
High‐yield isolation of murine microglia by mild trypsinization
Saura, J., Tusell, J. M., & Serratosa, J. (2003) · Glia · doi:10.1002/glia.10274 · Cited by 593
Kadl, A., Meher, A. K., Sharma, P. R., Lee, M. Y., Doran, A. C., Johnstone, S. R., Elliott, M. R., Gruber, F., Han, J., Chen, W., et al. (2010) · Circulation Research · doi:10.1161/circresaha.109.215715 · Cited by 573
Ghisletti, S., Huang, W., Ogawa, S., Pascual, G., Lin, M.-E., Willson, T. M., Rosenfeld, M. G., & Glass, C. K. (2007) · Molecular Cell · doi:10.1016/j.molcel.2006.11.022 · Cited by 561
HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis
Tall, A. R., Yvan-Charvet, L., Terasaka, N., Pagler, T., & Wang, N. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.03.001 · Cited by 540
Yoshikawa, T., Shimano, H., Amemiya-Kudo, M., Yahagi, N., Hasty, A. H., Matsuzaka, T., Okazaki, H., Tamura, Y., Iizuka, Y., Ohashi, K., et al. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.9.2991-3000.2001 · Cited by 534
Castrillo, A., Joseph, S. B., Vaidya, S. A., Haberland, M. E., Fogelman, A. M., Cheng, G., & Tontonoz, P. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00384-8 · Cited by 500
Blanc, M., Hsieh, W. Y., Robertson, K. A., Kropp, K. A., Forster, T., Shui, G., Lacaze, P., Watterson, S., Griffiths, S. J., Spann, N. J., et al. (2013) · Immunity · doi:10.1016/j.immuni.2012.11.004 · Cited by 411
Human White/Murine ABC8 mRNA Levels Are Highly Induced in Lipid-loaded Macrophages
Venkateswaran, A., Repa, J. J., Lobaccaro, J.-M. A., Bronson, A., Mangelsdorf, D. J., & Edwards, P. A. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.19.14700 · Cited by 386
Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors
Zelcer, N., Khanlou, N., Clare, R., Jiang, Q., Reed-Geaghan, E. G., Landreth, G. E., Vinters, H. V., & Tontonoz, P. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701096104 · Cited by 358
Involvement of Interferon-γ in Microglial-Mediated Loss of Dopaminergic Neurons
Mount, M. P., Lira, A., Grimes, D., Smith, P. D., Faucher, S., Slack, R. S., Anisman, H., Hayley, S. P., & Park, D. S. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.5321-06.2007 · Cited by 331
Sterol Intermediates from Cholesterol Biosynthetic Pathway as Liver X Receptor Ligands
Yang, C., McDonald, J. G., Patel, A. C., Zhang, Y., Umetani, M., Xu, F., Westover, E. J., Covey, D. F., Mangelsdorf, D. J., Cohen, J. C., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m603781200 · Cited by 320
Retinoid X receptors: common heterodimerization partners with distinct functions
Lefebvre, P., Benomar, Y., & Staels, B. (2010) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2010.06.009 · Cited by 309
Ghisletti, S., Huang, W. J. M., Jepsen, K., Benner, C. W., Hardiman, G., Rosenfeld, M. G., & Glass, C. K. (2009) · Genes & Development · doi:10.1101/gad.1773109 · Cited by 261
Wagner, B. L., Valledor, A. F., Shao, G. Q., Daige, C. L., Bischoff, E. D., Petrowski, M. L., Jepsen, K., Baek, S. H., Heyman, R. A., Rosenfeld, M. G., et al. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.16.5780-5789.2003 · Cited by 247
Self-citationVenteclef, N., Jakobsson, T., Ehrlund, A., Damdimopoulos, A., Mikkonen, L., Ellis, E., Nilsson, L.-M., Parini, P., Jänne, O. A., Gustafsson, J.-Å., et al. (2010) · Genes & Development · doi:10.1101/gad.545110 · Cited by 178
Self-citationNakamura, K., Kennedy, M. A., Baldán, Á., Bojanic, D. D., Lyons, K. M., & Edwards, P. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408652200 · Cited by 165
Lee, J. H., Park, S. M., Kim, O. S., Lee, C. S., Woo, J. H., Park, S. J., Joe, E.-H., & Jou, I. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.07.021 · Cited by 161 · cited 3×
“SUMOylated LXRs formed a complex with STAT1 resulting in inhibited recruitment of STAT1 to the Irf1 promoter during the response to IFN-g, without affecting STAT1 phosphorylation or its nuclear translocation (13).”
BackgroundInfluentialStevens, R. (2004) · Dictionary of Bioinformatics and Computational Biology · doi:10.1002/9780471650126.dob0273.pub2 · Cited by 153
Liver X receptors as regulators of macrophage inflammatory and metabolic pathways
A-González, N., & Castrillo, A. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.12.015 · Cited by 139
Jakobsson, T., Venteclef, N., Toresson, G., Damdimopoulos, A. E., Ehrlund, A., Lou, X., Sanyal, S., Steffensen, K. R., Gustafsson, J.-Α., & Treuter, E. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.05.006 · Cited by 138
Self-citationValledor, A. F., Comalada, M., Xaus, J., & Celada, A. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.10.7403 · Cited by 135
Self-citationMorales, J. R., Ballesteros, I., Deniz, J. M., Hurtado, O., Vivancos, J., Nombela, F., Lizasoaín, I., Castrillo, A., & Moro, M. Á. (2008) · Circulation · doi:10.1161/circulationaha.108.782300 · Cited by 117
Liver X receptor activation decreases the severity of experimental autoimmune encephalomyelitis
Hindinger, C., Hinton, D. R., Kirwin, S. J., Atkinson, R., Burnett, M. E., Bergmann, C. C., & Stohlman, S. A. (2006) · Journal of Neuroscience Research · doi:10.1002/jnr.21038 · Cited by 104
Cho, H. J., Kim, S., Jin, S. M., Hwang, E., Kim, Y. S., Huh, K., & Mook‐Jung, I. (2007) · Glia · doi:10.1002/glia.20451 · Cited by 98
Mangano, E. N., Litteljohn, D., So, R., Nelson, E., Peters, S., Bethune, C., Bobyn, J., & Hayley, S. P. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.02.016 · Cited by 97
Hao, X., Cao, D., Hu, Y., Li, X.-X., Liu, X., Xiao, J., Liao, D., Xiang, J., & Tang, C. (2008) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2008.07.029 · Cited by 82
Interferon-γ induces progressive nigrostriatal degeneration and basal ganglia calcification
Chakrabarty, P., Ceballos‐Diaz, C., Lin, W.-L., Beccard, A., Jansen‐West, K. R., McFarland, N. R., Janus, C., Dickson, D. W., Das, P., & Golde, T. E. (2011) · Nature Neuroscience · doi:10.1038/nn.2829 · Cited by 80
Cheng, O., Ostrowski, R. P., Liu, W., & Zhang, J. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.01.024 · Cited by 79
Liver X receptor agonists inhibit tissue factor expression in macrophages
Terasaka, N., Hiroshima, A., Ariga, A., Honzumi, S., Koieyama, T., Inaba, T., & Fujiwara, T. (2005) · FEBS Journal · doi:10.1111/j.1742-4658.2005.04599.x · Cited by 72
Ching, S., He, L., Lai, W., & Quan, N. (2004) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2004.06.001 · Cited by 70
Treatment with LXR agonists after focal cerebral ischemia prevents brain damage
Sironi, L., Mitro, N., Cimino, M., Gelosa, P., Guerrini, U., Tremoli, E., & Sáez, E. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.08.035 · Cited by 52
Pascual-García, M., Carbo, J. M. C. I., León, T. E., Matalonga, J., Out, R., van Berkel, T. J. C., Sarrias, M., Lozano, F., Celada, A., & Valledor, A. F. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1000585 · Cited by 35
Self-citationGene-resolution analysis of DNA copy number variation using oligonucleotide expression microarrays
Auer, H., Newsom, D. L., Nowak, N. J., McHugh, K. M., Singh, S., Yu, C. Y., Yang, Y., Wenger, G. D., Gastier, J. M., & Kornacker, K. (2007) · BMC Genomics · doi:10.1186/1471-2164-8-111 · Cited by 26
Self-citationKong, G., Peng, Z., Costanzo, C., Kristensson, K., & Bentivoglio, M. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02716-5 · Cited by 23
Post-transcriptional regulation of macrophage ABCA1, an early response gene to IFN-γ
León, M. L. A., Evans, G. F., Farmen, M. W., & Zuckerman, S. H. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.05.112 · Cited by 16
Cited by
Litvinchuk, A., Suh, J. H., Guo, J. L., Lin, K., Davis, S. S., Bien-Ly, N., Tycksen, E., Tabor, G. T., Remolina Serrano, J., Manis, M., et al. (2024) · Neuron · doi:10.1016/j.neuron.2023.10.023 · Cited by 161
Metadata
- Authors
- Pascual-García, M., Rué, L., León, T., Julve, J., Carbó, J. M., Matalonga, J., Auer, H., Celada, A., Escolà-Gil, J. C., Steffensen, K. R., Pérez-Navarro, E., & Valledor, A. F.
- Affiliations
- Nuclear Receptor Group, Department of Physiology and Immunology, School of Biology, University of Barcelona , 08028 Barcelona,
- Department of Cellular Biology, Immunology, and Neurosciences, School of Medicine, University of Barcelona , 08036 Barcelona,
- Institut d’Investigació Biomèdica Sant Pau , 08025 Barcelona,
- Functional Genomics Core Facility, Institute for Research in Biomedicine , Barcelona 08028,
- Macrophage Biology Group, Department of Physiology and Immunology, School of Biology, University of Barcelona , 08028 Barcelona,
- Department of Biosciences and Nutrition, Karolinska Institutet , SE-14183 Stockholm,
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-06
- Volume
- 190
- Issue
- 12
- Pages
- 6520-6532
- ISSN
- 0022-1767
- 1550-6606
- Cited by
- 51
- References
- 57
- Language
- en
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
