Down-regulation of surface receptors for TNF and IL-1 on circulating monocytes and granulocytes during human endotoxemia: effect of neutralization of endotoxin-induced TNF activity by infusion of a recombinant dimeric TNF receptor.
Leukocytes rapidly lose their surface receptors for TNF and IL-1 upon exposure to various stimuli in vitro. We sought to determine by FACS analysis changes in the expression of TNF receptors (TNFR) and type II IL-1R on circulating monocytes and granulocytes during endotoxemia in vivo, and the role of endogenous TNF in these changes. Twelve healthy subjects received an i.v. injection with LPS (2 ng/kg), directly preceded by a 30-min infusion of either a recombinant human dimeric TNFR type II-IgG fusion protein (TNFR:Fc; 6 mg/m2; n = 6) or vehicle (n = 6). LPS administration was associated with decreases in the expression of types I and II TNFR and type II IL-1R on both monocytes and granulocytes. Treatment with TNFR:Fc completely neutralized LPS-induced TNF activity (p < 0.0001 vs LPS only), modestly blunted the decrease in monocyte TNFR (p < 0.05), but did not influence reduced expression of granulocyte TNFR or monocyte/granulocyte type II IL-1R. In separate experiments, rTNF added to whole blood reduced cellular type I and type II TNFR expression by an effect on the type I TNFR; TNF did not (monocytes) decrease or only marginally (granulocytes) decreased type II IL-1R expression. LPS induces down-modulation of monocyte and granulocyte receptors for TNF and IL-1 in humans in vivo. TNF is involved in reduced monocyte TNFR expression during endotoxemia.
van der Poll
T
T
Cornell University Medical College, Department of Surgery, New York, NY 10021, USA.
Coyle
S M
SM
Kumar
A
A
Barbosa
K
K
Agosti
J M
JM
Lowry
S F
SF
D000328:Adult; D001833:Body Temperature Regulation; D019281:Dimerization; D015536:Down-Regulation; D019446:Endotoxemia / Q000378:metabolism*; D006098:Granulocytes / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009000:Monocytes / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D008070:Lipopolysaccharides; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha