title: Sepsis Patients Display a Reduced Capacity to Activate Nuclear Factor-κB in Multiple Cell Types.
abstract: OBJECTIVE
  Sepsis is a complex clinical condition associated with high morbidity and mortality. A distinctive feature of sepsis is the reduced capacity of leukocytes to release proinflammatory cytokines in response to ex vivo stimulation. Cellular signaling events leading to immunosuppression in sepsis are not well defined. We investigated cell-specific signaling events underlying the immunosuppressed phenotype in sepsis.
  
  
  METHODS
  Ex vivo study.
  
  
  METHODS
  ICU of an academic hospital.
  
  
  METHODS
  Nineteen patients with sepsis and 19 age-matched healthy controls.
  
  
  METHODS
  None.
  
  
  RESULTS
  The phosphorylation state of p38 mitogen activated protein kinase and nuclear factor kappa-light-chain-enhancer of activated B cells were determined in ex vivo stimulated CD4 T cells, CD8 T cells, B cells, monocytes, and neutrophils. Messenger RNA expression levels of p38 mitogen activated protein kinase and nuclear factor kappa-light-chain-enhancer of activated B cells and negative regulators tumor necrosis factor-α-induced protein 3 (A20) and mitogen activated protein kinase phosphatase-1 were determined in neutrophils and peripheral blood mononuclear cells. Upon ex vivo stimulation, monocytes of sepsis patients were less capable in phosphorylating nuclear factor kappa-light-chain-enhancer of activated B cells. Sepsis was also associated with reduced phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells in stimulated B cells, CD4 and CD8 T cells. Messenger RNA expression levels of nuclear factor kappa-light-chain-enhancer of activated B cells and A20 were diminished in peripheral blood mononuclear cells of sepsis patients, whereas p38 mitogen activated protein kinase messenger RNA was up-regulated. In neutrophils of sepsis patients, mitogen activated protein kinase phosphatase-1 messenger RNA levels were down-regulated.
  
  
  CONCLUSIONS
  Sepsis-induced immunosuppression associates with a defect in the capacity to phosphorylate nuclear factor kappa-light-chain-enhancer of activated B cells in lymphoid cells and monocytes.
authors.affiliation: 1Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 2Center for Infection and Immunity Amsterdam, Amsterdam, The Netherlands. 3Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 4Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 5Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Arie J
authors.initials: AJ
authors.lastname: Hoogendijk
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Garcia-Laorden
authors.forename: Lonneke A
authors.initials: LA
authors.lastname: van Vught
authors.forename: Maryse A
authors.initials: MA
authors.lastname: Wiewel
authors.forename: Hakima
authors.initials: H
authors.lastname: Belkasim-Bohoudi
authors.forename: JanWillem
authors.initials: J
authors.lastname: Duitman
authors.forename: Janneke
authors.initials: J
authors.lastname: Horn
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Schultz
authors.forename: Brendon P
authors.initials: BP
authors.lastname: Scicluna
authors.forename: Cornelis
authors.initials: C
authors.lastname: van 't Veer
authors.forename: Alex F
authors.initials: AF
authors.lastname: de Vos
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000368:Aged; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016131:Lymphocyte Subsets / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger; D018805:Sepsis / Q000276:immunology*; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases