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Interleukin-1 modulation of cytokine receptors on human neutrophils: in
vitro and in vivo studies
JH Shieh, M Gordon, A Jakubowski, RH Peterson, JL Gabrilove and MA Moore
James Ewing Laboratory of Developmental Hematopoiesis, Memorial Sloan-
Kettering Cancer Center, New York.
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.
Volume 81,
Issue 7,
pp. 1745-1754,
04/01/1993
Copyright © 1993 by The American Society of Hematology
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