Sustained release or high levels of interleukin-1 (IL-1) and/or tumor necrosis factor (TNF), as observed after endotoxin challenge, can produce a variety of toxicities. Naturally occurring inhibitors to IL-1 and TNF, IL-1 receptor antagonist (IL-1ra) and soluble TNF receptor forms, have been detected. These proteins may function to buffer or limit the effects of these cytokines as part of a regulatory network. As part of a clinical trial of recombinant human interleukin-1β (rhIL-1β), serial plasma samples were obtained from 6 patients with metastatic melanoma treated with 30-min infusions of rhIL-1β for 5 consecutive days. The presence of circulating IL-1 receptor antagonist and soluble 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-1β infusion. On each day of the treatment, the secretion of IL-1ra and release of TNF-R55-BP was observed, but there was no accumulation above baseline value for IL-1ra before each of the 5 daily infusions. Although there was a steady decrease of the 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 patients had measurable levels of TNF-α, but no correlation to TNF-binding proteins was observed. Our data show that early after rhIL-1β infusion the induction of IL-1ra secretion, as well as TNF-binding protein release, is observed.


This study was supported by NIH Grant RR00070 for the General Clinical Research Center at Stanford University Medical Center, CA-17963 to H. F. S., and a grant from Syntex Research, Palo Alto, CA. This study was supported in part by the Swedish Cancer Foundation. M. J. B. was supported by a grant from the Krebsliga beider Basel, Switzerland. F. M. T. is a Clinical Investigator, Department of Veterans Affairs.

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