title: Unopposed interleukin-1 is necessary for increased plasma cytokine and eicosanoid levels to develop in severe sepsis.
abstract: OBJECTIVE
  The purpose of the study was to identify the changes in plasma prostaglandin, leukotriene, and cytokine levels during clinical severe sepsis for which interleukin-1 was necessary.
  
  
  BACKGROUND
  Circulating prostaglandins, leukotrienes, and cytokines have been implicated as causative agents of systemic inflammation due to sepsis. However, interactions between interleukin-1 and the other cytokine and eicosanoid mediators of severe sepsis are not well-defined.
  
  
  METHODS
  As part of two sequential multisite, prospective, randomized, double-blind, placebo-controlled clinical trials, 37 patients with severe sepsis received interleukin-1 receptor antagonist (IL-1ra) 100-mg bolus followed by 2 mg/kg per hour intravenously for 72 hours (n = 20) or placebo (n = 17). Plasma thromboxane B2 (TxB2), prostaglandin 6-keto-F1alpha (PGI), leukotriene B4 (LTB4), leukotriene C4D4E4 (LTC4D4E4), interleukin-1 beta (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) were measured by enzyme-linked immunosorbent assay before study drug infusion (baseline) and at 24, 48, and 72 hours after the beginning of the study drug infusion.
  
  
  RESULTS
  Differences between placebo and IL-1ra for plasma LTB4 were not significant, but only IL-1ra LTB4 increased from baseline. Plasma TxB2, PGI, LTC4D4E4, TNF, and IL-6, expressed as % baseline, decreased significantly in patients receiving IL-1ra compared with the placebo group (p < 0.05), whereas plasma IL-1 increased significantly.
  
  
  CONCLUSIONS
  Interleukin-1 may be a necessary mediator of increased circulating PGI, TxB2, LTC4D4E4, TNF, and IL-6 levels in patients with severe sepsis. Plasma IL-1 and LTB4 are increased with infusion of IL-1 receptor antagonist. The clinical significance of IL-1 in modifying circulating eicosanoid and cytokine concentrations in clinical sepsis is not clear from the data.
authors.affiliation: Department of Surgery, Cooper Hospital/University Medical Center, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School at Camden, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Slotman
authors.forename: J V
authors.initials: JV
authors.lastname: Quinn
authors.forename: P C
authors.initials: PC
authors.lastname: Wry
authors.forename: C E
authors.initials: CE
authors.lastname: Brathwaite
authors.forename: B M
authors.initials: BM
authors.lastname: Friedman
mesh_terms: D016207:Cytokines / Q000097:blood*; D004311:Double-Blind Method; D015777:Eicosanoids / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012795:Sialoglycoproteins / Q000627:therapeutic use*; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood* / Q000209:etiology / Q000628:therapy*
chemical_list: D016207:Cytokines; D015777:Eicosanoids; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins