title: IL-10 Production in Macrophages Is Regulated by a TLR-Driven CREB-Mediated Mechanism That Is Linked to Genes Involved in Cell Metabolism.
abstract: IL-10 is produced by macrophages in diverse immune settings and is critical in limiting immune-mediated pathology. In helminth infections, macrophages are an important source of IL-10; however, the molecular mechanism underpinning production of IL-10 by these cells is poorly characterized. In this study, bone marrow-derived macrophages exposed to excretory/secretory products released by Schistosoma mansoni cercariae rapidly produce IL-10 as a result of MyD88-mediated activation of MEK/ERK/RSK and p38. The phosphorylation of these kinases was triggered by TLR2 and TLR4 and converged on activation of the transcription factor CREB. Following phosphorylation, CREB is recruited to a novel regulatory element in the Il10 promoter and is also responsible for regulating a network of genes involved in metabolic processes, such as glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation. Moreover, skin-resident tissue macrophages, which encounter S. mansoni excretory/secretory products during infection, are the first monocytes to produce IL-10 in vivo early postinfection with S. mansoni cercariae. The early and rapid release of IL-10 by these cells has the potential to condition the dermal microenvironment encountered by immune cells recruited to this infection site, and we propose a mechanism by which CREB regulates the production of IL-10 by macrophages in the skin, but also has a major effect on their metabolic state.
authors.affiliation: Department of Biology, Centre for Immunology and Infection, University of York, York YO10 5DD, United Kingdom.
authors.forename: David E
authors.initials: DE
authors.lastname: Sanin
authors.affiliation: Department of Biology, Centre for Immunology and Infection, University of York, York YO10 5DD, United Kingdom.
authors.forename: Catriona T
authors.initials: CT
authors.lastname: Prendergast
authors.affiliation: Department of Biology, Centre for Immunology and Infection, University of York, York YO10 5DD, United Kingdom adrian.mountford@york.ac.uk.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Mountford
mesh_terms: D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000276:immunology; D004734:Energy Metabolism / Q000235:genetics; D004789:Enzyme Activation / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D053765:Interleukin-12 Subunit p35 / Q000096:biosynthesis; D020930:MAP Kinase Kinase Kinases / Q000235:genetics; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012550:Schistosoma mansoni / Q000276:immunology; D012555:Schistosomiasis mansoni / Q000276:immunology / Q000469:parasitology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D051996:Transcription Factor RelA / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C556062:IL10 protein, mouse; C508859:Il12a protein, mouse; D053765:Interleukin-12 Subunit p35; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011518:Proto-Oncogene Proteins; C498144:Rela protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse