INDUCTION OF CIRCULATING AND ERYTHROCYTE-BOUND IL-8 BY IL-2 IMMUNOTHERAPY AND SUPPRESSION OF ITS IN-VITRO PRODUCTION BY IL-1-RECEPTOR ANTAGONIST AND SOLUBLE TUMOR-NECROSIS-FACTOR RECEPTOR (P75) CHIMERA
H. Tilg et al., INDUCTION OF CIRCULATING AND ERYTHROCYTE-BOUND IL-8 BY IL-2 IMMUNOTHERAPY AND SUPPRESSION OF ITS IN-VITRO PRODUCTION BY IL-1-RECEPTOR ANTAGONIST AND SOLUBLE TUMOR-NECROSIS-FACTOR RECEPTOR (P75) CHIMERA, The Journal of immunology, 151(6), 1993, pp. 3299-3307
The objective of this study was 1) to investigate the in vivo producti
on of IL-8 in patients undergoing IL-2 immunotherapy and 2) to study t
he influence of IL-1Ra, soluble TNF receptor p75 (TNFsRp75), and a TNF
sRp75-Fc fusion protein on IL-2-induced IL-8 production in vitro. Circ
ulating IL-8 was assessed both in plasma and erythrocyte lysates prepa
red from patients undergoing IL-2 immunotherapy. IL-8 was detectable i
n the plasma within 2-4 h after the first IL-2 infusion, reached a pea
k level after 4 h, and declined rapidly to undetectable within 8 h. Er
ythrocyte-bound IL-8 was also detected within 4 h of the first IL-2 do
se, but levels were higher than those measured in plasma and remained
elevated long after the plasma levels had become undetectable. On day
4 of therapy, the increases in both plasma and the erythrocyte-lysate
IL-8 levels induced by an IL-2 injection were less pronounced than on
day 1. Although IL-1Ra and TNFsRp75-Fc individually had only a modest
suppressive effect on IL-2-induced IL-8 production by PBMC in vitro, t
he combination of IL-1Ra and TNFsRp75-Fc markedly down-regulated IL-2-
induced IL-8 synthesis and steady-state mRNA levels. TNFsRp75 had no e
ffect on IL-2-induced IL-8 synthesis. Our studies suggest that the tra
nsient detection of IL-8 in plasma early in the course of IL-2 treatme
nt is due to erythrocyte sequestration and that suppressed synthesis,
due in part to high levels of circulating IL-1 and TNF antagonists, ma
y play a role later in the course of treatment.