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,
,§
*
Department of Microbiology, Immunology, and Molecular Genetics,
Division of Dermatology,
Molecular Biology Institute, and
§
Howard Hughes Medical Institute, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095; and
¶
Immunobiology Center, Mount Sinai School of Medicine, New York, NY 10029
IL-10 is an antiinflammatory cytokine secreted by activated macrophages and Th2 cells. IL-10 secretion promotes the down-regulation of proinflammatory cytokine synthesis and the development of Th2 responses. In macrophages, proinflammatory cytokines appear to be induced by similar mechanisms, but the IL-10 induction mechanisms have not been examined. We have analyzed the murine IL-10 promoter in the RAW264.7 macrophage line activated with LPS. A comprehensive mutant analysis revealed only one element upstream of the core promoter that was essential for promoter induction. A refined mutant analysis localized this element to nucleotides -89 to -78, and gel shift experiments revealed that it represents a nonconsensus binding site for Sp1. The functional relevance of Sp1 was supported by the high affinity of the interaction, the close correlation between the nucleotides required for Sp1 binding and promoter function, and the ability of an Sp1 consensus sequence to substitute for the -89/-78 promoter sequence. Evidence that Sp1 may be a target of signaling pathways involved in IL-10 induction was provided by the exclusive requirement for the Sp1 binding site, by the ability of the Sp1 site to confer induction to a heterologous promoter, and by the delineation of an Sp1 domain that can mediate induction. No relevant contribution from Rel, C/EBP (CCAAT/enhancer-binding protein), or AP-1 binding sites, which regulate most proinflammatory cytokine promoters, was observed. Together, these results demonstrate that IL-10 gene regulation is distinct from the regulation of proinflammatory cytokine genes, and suggest that Sp1 may be a central mediator of IL-10 induction.
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R. L. Chelvarajan, S. M. Collins, I. E. Doubinskaia, S. Goes, J. Van Willigen, D. Flanagan, W. J. S. de Villiers, J. S. Bryson, and S. Bondada Defective macrophage function in neonates and its impact on unresponsiveness of neonates to polysaccharide antigens J. Leukoc. Biol., June 1, 2004; 75(6): 982 - 994. [Abstract] [Full Text] [PDF]
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H. Zhou, H. Xiong, H. Li, S. E. Plevy, P. D. Walden, M. Sassaroli, G. D. Prestwich, and J. C. Unkeless Microtubule-Associated Serine/Threonine Kinase-205 kDa and Fc{gamma} Receptor Control IL-12 p40 Synthesis and NF-{kappa}B Activation J. Immunol., February 15, 2004; 172(4): 2559 - 2568. [Abstract] [Full Text] [PDF]
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M. N. Bradley, L. Zhou, and S. T. Smale C/EBP{beta} Regulation in Lipopolysaccharide-Stimulated Macrophages Mol. Cell. Biol., July 15, 2003; 23(14): 4841 - 4858. [Abstract] [Full Text] [PDF]
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Y.-W. Liu, H.-P. Tseng, L.-C. Chen, B.-K. Chen, and W.-C. Chang Functional Cooperation of Simian Virus 40 Promoter Factor 1 and CCAAT/Enhancer-Binding Protein {beta} and {delta} in Lipopolysaccharide-Induced Gene Activation of IL-10 in Mouse Macrophages J. Immunol., July 15, 2003; 171(2): 821 - 828. [Abstract] [Full Text] [PDF]
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L. Ziegler-Heitbrock, M. Lotzerich, A. Schaefer, T. Werner, M. Frankenberger, and E. Benkhart IFN-{alpha} Induces the Human IL-10 Gene by Recruiting Both IFN Regulatory Factor 1 and Stat3 J. Immunol., July 1, 2003; 171(1): 285 - 290. [Abstract] [Full Text] [PDF]
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P. Lefevre, S. Melnik, N. Wilson, A. D. Riggs, and C. Bonifer Developmentally Regulated Recruitment of Transcription Factors and Chromatin Modification Activities to Chicken Lysozyme cis-Regulatory Elements In Vivo Mol. Cell. Biol., June 15, 2003; 23(12): 4386 - 4400. [Abstract] [Full Text] [PDF]
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S. Goriely, D. Demonte, S. Nizet, D. De Wit, F. Willems, M. Goldman, and C. Van Lint Human IL-12(p35) gene activation involves selective remodeling of a single nucleosome within a region of the promoter containing critical Sp1-binding sites Blood, June 15, 2003; 101(12): 4894 - 4902. [Abstract] [Full Text] [PDF]
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J.-D. Ji, I. Tassiulas, K.-H. Park-Min, A. Aydin, I. Mecklenbrauker, A. Tarakhovsky, L. Pricop, J. E. Salmon, and L. B. Ivashkiv Inhibition of Interleukin 10 Signaling after Fc Receptor Ligation and during Rheumatoid Arthritis J. Exp. Med., June 2, 2003; 197(11): 1573 - 1583. [Abstract] [Full Text] [PDF]
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T. Ronni, V. Agarwal, M. Haykinson, M. E. Haberland, G. Cheng, and S. T. Smale Common Interaction Surfaces of the Toll-Like Receptor 4 Cytoplasmic Domain Stimulate Multiple Nuclear Targets Mol. Cell. Biol., April 1, 2003; 23(7): 2543 - 2555. [Abstract] [Full Text] [PDF]
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 H. Tagoh, R. Himes, D. Clarke, P. J.M. Leenen, A. D. Riggs, D. Hume, and C. Bonifer Transcription factor complex formation and chromatin fine structure alterations at the murine c-fms (CSF-1 receptor) locus during maturation of myeloid precursor cells Genes & Dev., July 1, 2002; 16(13): 1721 - 1737. [Abstract] [Full Text] [PDF]
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S. Taniura, H. Kamitani, T. Watanabe, and T. E. Eling Transcriptional Regulation of Cyclooxygenase-1 by Histone Deacetylase Inhibitors in Normal Human Astrocyte Cells J. Biol. Chem., May 3, 2002; 277(19): 16823 - 16830. [Abstract] [Full Text] [PDF]
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A.-K. Yi, J.-G. Yoon, S.-J. Yeo, S.-C. Hong, B. K. English, and A. M. Krieg Role of Mitogen-Activated Protein Kinases in CpG DNA-Mediated IL-10 and IL-12 Production: Central Role of Extracellular Signal-Regulated Kinase in the Negative Feedback Loop of the CpG DNA-Mediated Th1 Response J. Immunol., May 1, 2002; 168(9): 4711 - 4720. [Abstract] [Full Text] [PDF]
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T. R. Hughes, T. S. Tengku-Muhammad, S. A. Irvine, and D. P. Ramji A Novel Role of Sp1 and Sp3 in the Interferon-gamma -mediated Suppression of Macrophage Lipoprotein Lipase Gene Transcription J. Biol. Chem., March 22, 2002; 277(13): 11097 - 11106. [Abstract] [Full Text] [PDF]
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 P.-L. Wang and K. Ohura PORPHYROMONAS GINGIVALIS LIPOPOLYSACCHARIDE SIGNALING IN GINGIVAL FIBROBLASTS-CD14 AND TOLL-LIKE RECEPTORS Critical Reviews in Oral Biology & Medicine, March 1, 2002; 13(2): 132 - 142. [Abstract] [Full Text] [PDF]
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S. Tavor, P. T. Vuong, D. J. Park, A. F. Gombart, A. H. Cohen, and H. P. Koeffler Macrophage functional maturation and cytokine production are impaired in C/EBPepsilon -deficient mice Blood, March 1, 2002; 99(5): 1794 - 1801. [Abstract] [Full Text] [PDF]
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A. Byrne and D. J. Reen Lipopolysaccharide Induces Rapid Production of IL-10 by Monocytes in the Presence of Apoptotic Neutrophils J. Immunol., February 15, 2002; 168(4): 1968 - 1977. [Abstract] [Full Text] [PDF]
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T. Wang, W. P. Lafuse, and B. S. Zwilling NF{kappa}B and Sp1 Elements Are Necessary for Maximal Transcription of Toll-like Receptor 2 Induced by Mycobacterium avium J. Immunol., December 15, 2001; 167(12): 6924 - 6932. [Abstract] [Full Text] [PDF]
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L. Salez, V. Balloy, N. van Rooijen, M. Lebastard, L. Touqui, F. X. McCormack, and M. Chignard Surfactant Protein A Suppresses Lipopolysaccharide-Induced IL-10 Production by Murine Macrophages J. Immunol., May 15, 2001; 166(10): 6376 - 6382. [Abstract] [Full Text] [PDF]
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 M. Frankenberger, B. Passlick, T. Hofer, M. Siebeck, K. L. Maier, and L. H. W. Ziegler-Heitbrock Immunologic Characterization of Normal Human Pleural Macrophages Am. J. Respir. Cell Mol. Biol., September 1, 2000; 23(3): 419 - 426. [Abstract] [Full Text]
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W. Ma, W. Lim, K. Gee, S. Aucoin, D. Nandan, M. Kozlowski, F. Diaz-Mitoma, and A. Kumar The p38 Mitogen-activated Kinase Pathway Regulates the Human Interleukin-10 Promoter via the Activation of Sp1 Transcription Factor in Lipopolysaccharide-stimulated Human Macrophages J. Biol. Chem., April 20, 2001; 276(17): 13664 - 13674. [Abstract] [Full Text] [PDF]
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