title: IL-1 beta does not cause neutrophil degranulation but does lead to IL-6, IL-8, and nitrite/nitrate release when used in patients with cancer.
abstract: The use of IL-1 in humans is associated with dose-limiting toxicity which resembles that of TNF-alpha or IL-2. Activation of neutrophils is thought to contribute to the toxicity caused by these two cytokines. We studied the effect of IL-1 in vivo on changes in neutrophil numbers and neutrophil degranulation as well as on the formation of neutrophil agonists, such as complement activation products, and on levels of TNF, IL-6, IL-8, and nitrite/nitrate (as a measure of nitric oxide production). Six patients with metastatic melanoma were treated with 3 ng/kg recombinant human IL-1 beta daily. One hour after the start of the 30-min IL-1 infusion, which caused mild cardiovascular toxicity, plasma levels of IL-6 reached a peak of 25 +/- 9 ng/L (mean +/- SEM), IL-8 reached a peak of 311 +/- 100 ng/L at 2 h, and nitrite/nitrate peaked after 10 h to 89 +/- 27 mumol/L. IL-1 did not induce significant changes in plasma levels of TNF or of the complement activation products C3a and C4b/c. Although IL-1 induced neutrophilia, levels of elastase and lactoferrin did not change. The failure of IL-1 to degranulate neutrophils was confirmed in an ex vivo model with whole blood culture in which doses of up to 100 microgram/L IL-1 beta or IL-1 alpha failed to induce significant elastase or lactoferrin release, whereas TNF, tested as a positive control, was able to do so. These results demonstrate that, unlike TNF, IL-1 does not cause neutrophil degranulation in man, despite its ability to cause neutrophilia and the rapid release of IL-6, IL-8, and nitrite/nitrate.
authors.affiliation: Department of Medical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, University of Amsterdam.
authors.forename: A C
authors.initials: AC
authors.lastname: Ogilvie
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
authors.forename: J
authors.initials: J
authors.lastname: Wagstaff
authors.forename: G J
authors.initials: GJ
authors.lastname: van Mierlo
authors.forename: A J
authors.initials: AJ
authors.lastname: Erenberg
authors.forename: L L
authors.initials: LL
authors.lastname: Thomsen
authors.forename: K
authors.initials: K
authors.lastname: Hoekman
authors.forename: E M
authors.initials: EM
authors.lastname: Rankin
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015550:Cell Degranulation / Q000187:drug effects*; D003167:Complement Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000009:adverse effects / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000097:blood* / Q000378:metabolism; D016209:Interleukin-8 / Q000097:blood* / Q000378:metabolism; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000556:secondary / Q000628:therapy; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D009566:Nitrates / Q000097:blood*; D009573:Nitrites / Q000097:blood*
chemical_list: D000970:Antineoplastic Agents; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D009566:Nitrates; D009573:Nitrites