title: IL-27 enhances LPS-induced proinflammatory cytokine production via upregulation of TLR4 expression and signaling in human monocytes.
abstract: IL-27, which is produced by activated APCs, bridges innate and adaptive immunity by regulating the development of Th cells. Recent evidence supports a role for IL-27 in the activation of monocytic cells in terms of inflammatory responses. Indeed, proinflammatory and anti-inflammatory activities are attributed to IL-27, and IL-27 production itself is modulated by inflammatory agents such as LPS. IL-27 primes LPS responses in monocytes; however, the molecular mechanism behind this phenomenon is not understood. In this study, we demonstrate that IL-27 priming results in enhanced LPS-induced IL-6, TNF-α, MIP-1α, and MIP-1β expression in human primary monocytes. To elucidate the molecular mechanisms responsible for IL-27 priming, we measured levels of CD14 and TLR4 required for LPS binding. We determined that IL-27 upregulates TLR4 in a STAT3- and NF-κB-dependent manner. Immunofluorescence microscopy revealed enhanced membrane expression of TLR4 and more distinct colocalization of CD14 and TLR4 upon IL-27 priming. Furthermore, IL-27 priming enhanced LPS-induced activation of NF-κB family members. To our knowledge, this study is the first to show a role for IL-27 in regulating TLR4 expression and function. This work is significant as it reveals new mechanisms by which IL-27 can enhance proinflammatory responses that can occur during bacterial infections.
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Guzzo
authors.forename: Amit
authors.initials: A
authors.lastname: Ayer
authors.forename: Sameh
authors.initials: S
authors.lastname: Basta
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Banfield
authors.forename: Katrina
authors.initials: K
authors.lastname: Gee
mesh_terms: D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002469:Cell Separation; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000096:biosynthesis; D054407:Chemokine CCL4 / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D015850:Interleukin-6 / Q000096:biosynthesis; D007378:Interleukins / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D054405:Chemokine CCL3; D054407:Chemokine CCL4; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D007378:Interleukins; D008070:Lipopolysaccharides; C464565:MYDGF protein, human; D012333:RNA, Messenger; C495345:TLR4 protein, human; C439524:TNF protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha