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Myeloid-derived NF-κB negative regulation of PU.1 and c/EBP-ß-driven pro-inflammatory cytokine production restrains LPS-induced shock.
Vanoni, Simone; Tsai, Yi-Ting; Waddell, Amanda; Waggoner, Lisa; Klarquist, Jared; Divanovic, Senad; Hoebe, Kasper; Steinbrecher, Kris A; Hogan, Simon P.
Afiliación
  • Vanoni S; 1 Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • Tsai YT; 1 Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • Waddell A; 1 Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • Waggoner L; 1 Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • Klarquist J; 2 Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • Divanovic S; 2 Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • Hoebe K; 2 Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • Steinbrecher KA; 3 Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • Hogan SP; 1 Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Innate Immun ; 23(2): 175-187, 2017 02.
Article en En | MEDLINE | ID: mdl-27932520
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-1ß, 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-1ß 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-1ß and IL-6. We show that the elevated pro-inflammatory cytokine secretion was due, in part, to increased accumulation of IL-1ß mRNA and protein in activated inflammatory MΦs. The increased IL-1ß was linked with heightened binding of PU.1 and CCAAT/enhancer binding protein-ß 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Macrófagos Peritoneales / Sepsis / Factor de Transcripción ReIA / Macrófagos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Innate Immun Asunto de la revista: ALERGIA E IMUNOLOGIA / BACTERIOLOGIA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Macrófagos Peritoneales / Sepsis / Factor de Transcripción ReIA / Macrófagos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Innate Immun Asunto de la revista: ALERGIA E IMUNOLOGIA / BACTERIOLOGIA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos