title: Interleukin-1 modulation of cytokine receptors on human neutrophils: in vitro and in vivo studies.
abstract: Interleukin-1 (IL-1) modulation of cytokine receptors (human IL-1 receptor [hIL-1R], human granulocyte colony-stimulating factor [hG-CSFR], human granulocyte-macrophage CSF receptor [hGM-CSFR], and human tumor necrosis factor receptor [hTNFR]) on human neutrophils was studied both in vitro and in vivo. In vitro, incubation of neutrophils with IL-1 at 37 degrees C for 0.5 or 8 hours caused a reduction of IL-1 binding in a dose-dependent manner, but did not demonstrably affect binding of the other cytokines tested. In vivo, neutrophils from patients with gastrointestinal malignancies who were participating in a clinical trial of recombinant human IL-1 beta (rhIL-1 beta) demonstrated modulation of cytokine receptors in an IL-1 beta dose- and time-dependent manner. At the two highest dose levels of IL-1 beta (0.068 and 0.1 microgram/kg), reduction (> 40%) of G-CSF binding and elevation (twofold to sixfold) of IL-1 binding to neutrophils was observed after 1 hour and 4 to 8 hours, respectively. In addition, IL-1 beta rapidly elevated G-CSF and glucocorticoid levels in plasma. Patients at the lowest dose level (0.002 microgram/kg) had a less dramatic change in these parameters. Further in vitro studies showed that synthetic glucocorticoids and G-CSF synergistically up-modulated IL-1 binding to neutrophils in a dose- and time-dependent manner. Scatchard analysis of binding data showed that this in vitro synergistic modulation was due to an increase in receptor numbers, rather than an increase in binding affinity. In addition, both human umbilical cord blood and bone marrow neutrophils responded to G-CSF and dexamethasone (Dex) with a superadditive increase in IL-1 binding. Therefore, one of mechanisms for IL-1 up-modulation of IL-1R on human neutrophils in vivo was due to the fact that IL-1 rapidly elevates serum levels of G-CSF and glucocorticoids.
authors.affiliation: James Ewing Laboratory of Developmental Hematopoiesis, Memorial Sloan-Kettering Cancer Center, New York.
authors.forename: J H
authors.initials: JH
authors.lastname: Shieh
authors.forename: M
authors.initials: M
authors.lastname: Gordon
authors.forename: A
authors.initials: A
authors.lastname: Jakubowski
authors.forename: R H
authors.initials: RH
authors.lastname: Peterson
authors.forename: J L
authors.initials: JL
authors.lastname: Gabrilove
authors.forename: M A
authors.initials: MA
authors.lastname: Moore
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000187:drug effects; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000187:drug effects; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000187:drug effects; D017472:Receptors, Interleukin-1 / Q000187:drug effects*; D018124:Receptors, Tumor Necrosis Factor; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007375:Interleukin-1; D011956:Receptors, Cell Surface; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D016179:Granulocyte Colony-Stimulating Factor; D003907:Dexamethasone