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 objective of this study was 1) to investigate the in vivo production of IL-8 in patients undergoing IL-2 immunotherapy and 2) to study the influence of IL-1Ra, soluble TNF receptor p75 (TNFsRp75), and a TNFsRp75-Fc fusion protein on IL-2-induced IL-8 production in vitro. Circulating IL-8 was assessed both in plasma and erythrocyte lysates prepared from patients undergoing IL-2 immunotherapy. IL-8 was detectable in the plasma within 2-4 h after the first IL-2 infusion, reached a peak level after 4 h, and declined rapidly to undetectable within 8 h. Erythrocyte-bound IL-8 was also detected within 4 h of the first IL-2 dose, 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, the combination of IL-1Ra and TNFsRp75-Fc markedly down-regulated IL-2-induced IL-8 synthesis and steady-state mRNA levels. TNFsRp75 had no effect on IL-2-induced IL-8 synthesis. Our studies suggest that the transient detection of IL-8 in plasma early in the course of IL-2 treatment is due to erythrocyte sequestration and that suppressed synthesis, due in part to high levels of circulating IL-1 and TNF antagonists, may play a role later in the course of treatment.
Division of Hematology-Oncology, New England Medical Center, Boston, MA.
H
H
Tilg
L
L
Shapiro
M B
MB
Atkins
C A
CA
Dinarello
J W
JW
Mier
D002118:Calcium / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000628:therapy; D004912:Erythrocytes / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007167:Immunotherapy; D053590:Interleukin 1 Receptor Antagonist Protein; D007376:Interleukin-2 / Q000235:genetics / Q000627:therapeutic use*; D016209:Interleukin-8 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008213:Lymphocyte Activation; D008545:Melanoma / Q000628:therapy; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology*
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007376:Interleukin-2; D016209:Interleukin-8; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D012795:Sialoglycoproteins; D002118:Calcium