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 immunotherapy with IL-2 results in detectable levels of circulating IL-1 and TNF antagonists and whether the levels achieved in vivo are sufficient to affect the generation of secondary proinflammatory cytokines such as IL-1 beta and TNF-alpha. We also sought to determine the extent to which endogenous TNF mediates the generation of an IL-1 antagonist by IL-2-activated PBMCs. In patients undergoing high dose IL-2 immunotherapy, plasma IL-1 receptor antagonist (IL-1ra) levels rose dramatically after the first IL-2 injection, reaching a plateau of 11.03 +/- 0.92 ng/ml within 4 h. TNF-soluble receptor p55 (TNFsRp55) was also detected in the plasma shortly after initiating treatment, and the levels progressively increased throughout the treatment course. PBMCs exposed to IL-2 expressed IL-1ra mRNA and secreted the IL-1ra protein, but neither PBMCs nor neutrophils shed TNFsRp55 in response to IL-2 or supernatants from IL-2-activated PBMCs. IL-1ra at concentrations achieved in the plasma during IL-2 immunotherapy (approximately 10 ng/ml) inhibited the in vitro production of IL-1 beta and TNF-alpha by IL-2-activated PBMCs by 65% and 30%, respectively. Although the monomeric receptor TNFsRp55 at concentrations achieved in the plasma had no effect on the in vitro production of IL-1ra, TNF-alpha, or IL-1 beta, the bivalent TNFsRp75-Fc chimera suppressed the generation of TNF and IL-1. IL-1ra synthesis was unaffected. These results suggest that the amount of IL-1ra generated in response to IL-2 is most likely sufficient to down-modulate the production of proinflammatory cytokines.
Tilg
H
H
Department of Medicine, New England Medical Center, Boston, MA 02111.
Shapiro
L
L
Vannier
E
E
Poutsiaka
D D
DD
Trehu
E
E
Atkins
M B
MB
Dinarello
C A
CA
Mier
J W
JW
D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D007376:Interleukin-2 / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D012795:Sialoglycoproteins / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D016207:Cytokines; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D007376:Interleukin-2; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha