INTERLEUKIN-1-BETA INDUCES INTERLEUKIN-1 RECEPTOR ANTAGONIST AND TUMOR-NECROSIS-FACTOR BINDING-PROTEIN IN HUMANS

Sustained release or high levels of interleukin-1 (IL-1) and/or tumor necrosis factor (TNF), as observed after endotoxin challenge, can prod uce a variety of toxicities. Naturally occurring inhibitors to IL-1 an d TNF, IL-1 receptor antagonist (IL-1ra) and soluble TNF receptor form s, have been detected. These proteins may function to buffer or limit the effects of these cytokines as part of a regulatory network. As par t of a clinical trial of recombinant human interleukin-1beta (rhIL-1be ta), serial plasma samples were obtained from 6 patients with metastat ic melanoma treated with 30-min infusions of rhIL-1beta for 5 consecut ive days. The presence of circulating IL-1 receptor antagonist and sol uble TNF binding proteins (TNF-R55-BP and TNF-R75-BP) were assessed. A maximum 86-fold increase for IL-1ra, a 7-8-fold increase for TNF-R55- BP, and a 2-3-fold increase for TNF-R75-BP were seen 2-4 h, 1 h, and 4 h, respectively, after rhIL-1beta infusion. On each day of the treatm ent, the secretion of IL-1ra and release of TNF-R55-BP was observed, b ut there was no accumulation above baseline value for IL-1ra before ea ch of the 5 daily infusions. Although there was a steady decrease of t he 6-h postinfusion plasma levels for IL-1ra and TNF-R55-BP over the 5 treatment days, no increase of clinical side effects was noted. Two p atients had measurable levels of TNF-alpha, but no correlation to TNF- binding proteins was observed. Our data show that early after rhIL-1be ta infusion the induction of IL-1ra secretion, as well as TNF-binding protein release, is observed.