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 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.