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 FAGS a nalysis 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 prece ded by a 30-min infusion of either a recombinant human dimeric TNFR ty pe II-IgG fusion protein (TNFR:Fc; 6 mg/m(2); n = 6) or vehicle (n = 6 ), LPS administration was associated with decreases in the expression of types I and II TNFR and type I) IL-1R on both monocytes and granulo cytes. Treatment with TNFR:Fc completely neutralized LPS-induced TNF a ctivity (p < 0.0001 vs LPS only), modestly blunted the decrease in mon ocyte TNFR (p < 0.05), but did not influence reduced expression of gra nulocyte TNFR or monocyte/granulocyte type II IL-1R. In separate exper iments, 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 (monocyte s) decrease or only marginally (granulocytes) decreased type II IL-1R expression, LPS induces down-modulation of monocyte and granulocyte re ceptors for TNF and IL-1 in humans in vivo. TNF is involved in reduced monocyte TNFR expression during endotoxemia.