title: Myeloid-derived NF-κB negative regulation of PU.1 and c/EBP-β-driven pro-inflammatory cytokine production restrains LPS-induced shock.
abstract: Sepsis is a life-threatening event predominantly caused by Gram-negative bacteria. Bacterial infection causes a pronounced macrophage (MΦ) and dendritic cell activation that leads to excessive pro-inflammatory cytokine IL-1β, IL-6 and TNF-α production (cytokine storm), resulting in endotoxic shock. Previous experimental studies have revealed that inhibiting NF-κB signaling ameliorates disease symptoms; however, the contribution of myeloid p65 in endotoxic shock remains elusive. In this study, we demonstrate increased mortality in mice lacking p65 in the myeloid lineage (p65Δmye) compared with wild type mice upon ultra-pure LPS challenge. We show that increased susceptibility to LPS-induced shock was associated with elevated serum level of IL-1β and IL-6. Mechanistic analyses revealed that LPS-induced pro-inflammatory cytokine production was ameliorated in p65-deficient bone marrow-derived MΦs; however, p65-deficient 'activated' peritoneal MΦs exhibited elevated IL-1β and IL-6. We show that the elevated pro-inflammatory cytokine secretion was due, in part, to increased accumulation of IL-1β mRNA and protein in activated inflammatory MΦs. The increased IL-1β was linked with heightened binding of PU.1 and CCAAT/enhancer binding protein-β to Il1b and Il6 promoters in activated inflammatory MΦs. Our data provide insight into a role for NF-κB in the negative regulation of pro-inflammatory cytokines in myeloid cells.
authors.affiliation: 1 Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Vanoni
authors.affiliation: 1 Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Tsai
authors.affiliation: 1 Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Waddell
authors.affiliation: 1 Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Waggoner
authors.affiliation: 2 Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Klarquist
authors.affiliation: 2 Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Senad
authors.initials: S
authors.lastname: Divanovic
authors.affiliation: 2 Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Kasper
authors.initials: K
authors.lastname: Hoebe
authors.affiliation: 3 Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Kris A
authors.initials: KA
authors.lastname: Steinbrecher
authors.affiliation: 1 Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hogan
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018805:Sepsis / Q000139:chemically induced / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051996:Transcription Factor RelA; D000099232:Proto-Oncogene Protein Spi-1; C530718:CEBPA protein, mouse; C498144:Rela protein, mouse
keywords: Animal models; LPS; NF-κB; cytokines; macrophages