H. Tilg et al., INDUCTION OF CIRCULATING ANTAGONISTS TO IL-1 AND TNF BY IL-2 ADMINISTRATION AND THEIR EFFECTS ON IL-2-INDUCED CYTOKINE PRODUCTION IN-VITRO, The Journal of immunology, 152(6), 1994, pp. 3189-3198
The objectives of this study were to determine whether intensive immun
otherapy with IL-2 results in detectable levels of circulating IL-1 an
d TNF antagonists and whether the levels achieved in vivo are sufficie
nt to affect the generation of secondary proinflammatory cytokines suc
h as IL-1 beta and TNF-alpha. We also sought to determine the extent t
o which endogenous TNF mediates the generation of an IL-1 antagonist b
y IL-2-activated PBMCs. In patients undergoing high dose IL-2 immunoth
erapy, plasma IL-1 receptor antagonist (IL-1ra) levels rose dramatical
ly after the first IL-2 injection, reaching a plateau of 11.03 +/- 0.9
2 ng/ml within 4 h. TNF-soluble receptor p55 (TNFsRp55) was also detec
ted in the plasma shortly after initiating treatment, and the levels p
rogressively increased throughout the treatment course. PBMCs exposed
to IL-2 expressed IL-1ra mRNA and secreted the IL-1ra protein, but nei
ther PBMCs nor neutrophils shed TNFsRp55 in response to IL-2 or supern
atants from IL-2-activated PBMCs. IL-1ra at concentrations achieved in
the plasma during IL-2 immunotherapy (approximate to 10 ng/ml) inhibi
ted the in vitro production of IL-1 beta and TNF-alpha. by IL-2-activa
ted PBMCs by 65% and 30%, respectively. Although the monomeric recepto
r TNFsRp55 at concentrations achieved in the plasma had no effect on t
he in vitro production of IL-1ra, TNF-alpha, or IL-1 beta, the bivalen
t TNFsRp75-Fc chimera suppressed the generation of TNF and IL-1. IL-1r
a synthesis was unaffected. These results suggest that the amount of I
L-1ra generated in response to. IL-2 is most likely sufficient to down
-modulate the production of proinflammatory cytokines.