title: Tumor necrosis factor-enhanced leukotriene B4 generation and chemotaxis in human neutrophils.
abstract: In an in vivo study of five normal volunteers infused with endotoxin (20 U/kg of US reference endotoxin lot EC-5), increased neutrophil (PMN) generation of leukotriene B4 and chemotaxis to leukotriene B4 were found concomitantly with elevated plasma tumor necrosis factor (TNF) levels. To clarify the role of TNF in PMN activation, neutrophil responsiveness after in vitro treatment with TNF was examined. Neutrophils from seven normal subjects were incubated with TNF for 30 minutes and tested for chemotaxis to leukotriene B4, formyl-methionyl-leucyl-phenylalanine and zymosan-activated serum, or the calcium ionophore A23187 to assess leukotriene B4 generation. A range of 10(-13) to 10(-9) mol/L of TNF was used for these assays. When 10(-9) mol/L of TNF was used, the amount of leukotriene B4 that was produced was significantly greater than in control cells. The effect of TNF on PMN chemotaxis was uniformly inhibitory for the three stimuli at 10(-10) mol/L compared with untreated cells. At a picomolar range, PMN migration to leukotriene B4, but not to zymosan-activated serum or formyl-methionyl-leucyl-phenylalanine, was significantly increased over that of PMNs not exposed to TNF. This suggests that TNF has a specific facilitatory effect on PMN responsiveness for both leukotriene B4 production and chemotaxis to leukotriene B4 and may be the same signal for this phenomenon in endotoxemic patients.
authors.affiliation: Department of Surgery, Cornell University Medical College, New York.
authors.forename: J D
authors.initials: JD
authors.lastname: Meyer
authors.forename: R W
authors.initials: RW
authors.lastname: Yurt
authors.forename: R
authors.initials: R
authors.lastname: Duhaney
authors.forename: D G
authors.initials: DG
authors.lastname: Hesse
authors.forename: K J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: Y M
authors.initials: YM
authors.lastname: Fong
authors.forename: M
authors.initials: M
authors.lastname: Verma
authors.forename: G T
authors.initials: GT
authors.lastname: Shires
authors.forename: P
authors.initials: P
authors.lastname: Dineen
authors.forename: S F
authors.initials: SF
authors.lastname: Lowry
mesh_terms: D000001:Calcimycin / Q000008:administration & dosage / Q000493:pharmacokinetics; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000008:administration & dosage / Q000493:pharmacokinetics; D004926:Escherichia coli; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007975:Leukotriene B4 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000008:administration & dosage / Q000493:pharmacokinetics; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D013268:Stimulation, Chemical; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D015054:Zymosan / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; D000001:Calcimycin; D009240:N-Formylmethionine Leucyl-Phenylalanine; C044101:endotoxin, Escherichia coli; D015054:Zymosan