title: Processing Body Formation Limits Proinflammatory Cytokine Synthesis in Endotoxin-Tolerant Monocytes and Murine Septic Macrophages.
abstract: An anti-inflammatory phenotype with pronounced immunosuppression develops during sepsis, during which time neutrophils and monocytes/macrophages limit their Toll-like receptor 4 responses to bacterial lipopolysaccharide (LPS/endotoxin). We previously reported that during this endotoxin-tolerant state, distinct signaling pathways differentially repress transcription and translation of proinflammatory cytokines such as TNFα and IL-6. Sustained endotoxin tolerance contributes to sepsis mortality. While transcription repression requires chromatin modifications, a translational repressor complex of Argonaute 2 (Ago2) and RNA-binding motif protein 4 (RBM4), which bind the 3'-UTR of TNFα and IL-6 mRNA, limits protein synthesis. Here, we show that Dcp1 supports the assembly of the Ago2 and RBM4 repressor complex into cytoplasmic processing bodies (p-bodies) in endotoxin-tolerant THP-1 human monocytes following stimulation with LPS, resulting in translational repression and limiting protein synthesis. Importantly, this translocation process is reversed by Dcp1 knockdown, which restores TNFα and IL-6 protein levels. We also find this translational repression mechanism in primary macrophages of septic mice. Because p-body formation is a critical step in mRNA translation repression, we conclude that Dcp1 is a major component of the translational repression machinery of endotoxin tolerance and may contribute to sepsis outcome.
authors.affiliation: Department of Internal Medicine, East Tennessee State University College of Medicine, Johnson City, Tenn., USA.
authors.forename: Clara
authors.initials: C
authors.lastname: McClure
authors.forename: Laura
authors.initials: L
authors.lastname: Brudecki
authors.forename: Zhi Q
authors.initials: ZQ
authors.lastname: Yao
authors.forename: Charles E
authors.initials: CE
authors.lastname: McCall
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Gazzar
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D010450:Endopeptidases / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects* / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
chemical_list: C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; C560608:RBM44 protein, mouse; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4; D010450:Endopeptidases; C020071:dipeptidyl carboxypeptidase