title: Ketamine inhibits transcription factors activator protein 1 and nuclear factor-kappaB, interleukin-8 production, as well as CD11b and CD16 expression: studies in human leukocytes and leukocytic cell lines.
abstract: BACKGROUND
  Recent data indicate that ketamine exerts antiinflammatory actions. However, little is known about the signaling mechanisms involved in ketamine-induced immune modulation. In this study, we investigated the effects of ketamine on lipopolysaccharide-induced activation of transcription factors activator protein 1 (AP-1) and nuclear factor-kappaB (NF-kappaB) in human leukocyte-like cell lines and in human blood neutrophils.
  
  
  METHODS
  Electric mobility shift assays were used to investigate ketamine's effects on nuclear binding activity of both transcription factors in U937 cells, and a whole blood flow cytometric technique was used for AP-1 and NF-kappaB determination in leukocytes. Cell lines with different expression patterns of opioid and N-methyl-D-aspartate receptors were used for reverse transcription-polymerase chain reaction to investigate receptors involved in ketamine signaling. Ketamine's effect on interleukin-8 production was assessed in a whole blood assay.
  
  
  RESULTS
  Ketamine inhibited both transcription factors in a concentration-dependent manner. These effects did not depend on opiate or N-methyl-D-aspartate receptors. Ketamine also reduced interleukin-8 production in whole blood and expression of CD11b and CD16 on neutrophils.
  
  
  CONCLUSIONS
  The immunoinhibitory effects of ketamine are at least in part caused by inhibition of transcription factors NF-kappaB and AP-1, which regulate production of proinflammatory mediators. However, signaling mechanisms different from those present in the central nervous system are responsible for ketamine-mediated immunomodulation.
authors.affiliation: School of Clinical Science, University of Liverpool, The Duncan Building, Daulby St., Liverpool L69 3GA, UK. i.welters@chiru.med.uni-giessen.de
authors.forename: Ingeborg D
authors.initials: ID
authors.lastname: Welters
authors.forename: Georg
authors.initials: G
authors.lastname: Hafer
authors.forename: Axel
authors.initials: A
authors.lastname: Menzebach
authors.forename: Jörg
authors.initials: J
authors.lastname: Mühling
authors.forename: Christoph
authors.initials: C
authors.lastname: Neuhäuser
authors.forename: Paul
authors.initials: P
authors.lastname: Browning
authors.forename: Yannick
authors.initials: Y
authors.lastname: Goumon
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D039481:CD11b Antigen / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D058851:GPI-Linked Proteins; D018922:HL-60 Cells; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D007649:Ketamine / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D020298:U937 Cells; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D039481:CD11b Antigen; C508606:CXCL8 protein, human; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; C509295:ITGAM protein, human; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017452:Receptors, IgG; D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D018808:Transcription Factor AP-1; C433788:lipopolysaccharide, E. coli O26-B6; D007649:Ketamine