Effects of recombinant soluble type I interleukin-1 receptor on human inflammatory responses to endotoxin.
Effects of soluble recombinant human type I interleukin-1 receptor (sIL-1RI) were evaluated in 18 volunteers given intravenous endotoxin and randomized to placebo (n = 6), low-dose (n = 6), or high-dose (n = 6) sIL-1RI. Soluble IL-1RI decreased IL-1 beta (P = .001), but decreased IL-1ra (P = .0001), and resulted in 10-fold and 43-fold dose-related increases in sIL-1RI-IL-1ra complexes compared with placebo (P < or = .001). High-dose sIL-1RI was associated with increased levels of immunoactive tumor necrosis factor-alpha (P = .02), IL-8 (P = .0001), and cell-associated IL-1 beta (P = .047). C-reactive protein levels were higher after sIL-1RI than placebo (P = .035). Soluble IL-1RI decreased the severity of chills (P = .03), but did not alter other symptoms, changes in temperature, systemic hemodynamic responses, or changes in leukocyte and platelet number. Thus, sIL-1RI had no discernable antiinflammatory effect following endotoxin administration due in part to low levels of circulating IL-1 beta and neutralization of IL-1ra inhibitory function. This latter interaction represents an indirect mechanism of agonist activity elicited by sIL-1RI and may contribute to increases in inflammatory mediators, limiting therapy with sIL-1RI during endotoxemia.
Preas
H L
HL
Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892-1662, USA.
Reda
D
D
Tropea
M
M
Vandivier
R W
RW
Banks
S M
SM
Agosti
J M
JM
Suffredini
A F
AF
D000210:Acute-Phase Reaction; D000328:Adult; D001772:Blood Cell Count / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004731:Endotoxins / Q000009:adverse effects*; D005260:Female; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy*; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D007781:Lactoferrin / Q000032:analysis; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D012768:Shivering; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D016207:Cytokines; D004731:Endotoxins; C507763:IL1RN protein, human; D007155:Immunologic Factors; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D010446:Peptide Fragments; D017472:Receptors, Interleukin-1; D011993:Recombinant Fusion Proteins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D007781:Lactoferrin