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Cytokine regulation of colony-stimulating factor production in cultured
human synovial fibroblasts: I. Induction of GM-CSF and G-CSF production by
interleukin-1 and tumor necrosis factor
T Leizer, J Cebon, JE Layton and JA Hamilton
Department of Medicine, Royal Melbourne Hospital, University of Melbourne,
Parkville, Victoria, Australia.
The cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), induce
a dose-dependent production of both granulocyte-macrophage
colony-stimulating factor (GM-CSF) and granulocyte CSF (G-CSF) in cultured
human synovial cells, as measured by immunoassay. With IL-1, significant
levels of both CSFs were first detected within 6 to 12 hours, with a
maximum reached 24 to 48 hours after commencement of stimulation. A
synergistic effect was detected between IL-1 and TNF in production of both
CSFs in these cells. No evidence was obtained for the IL-1-induced effect
to be mediated by induction of endogenous TNF nor for the TNF-induced
stimulation to involve IL-1. IL-1-stimulated synovial cells were shown to
secrete biologically active GM-CSF and G- CSF, which were specifically
inhibited by their respective monoclonal antibodies. The transcription
inhibitor, actinomycin D, and protein synthesis inhibitor, cycloheximide,
inhibited the increase in GM-CSF and G-CSF production induced by IL-1 and
TNF. Finally, other cytokines, IL-3, interferon gamma (IFN gamma), IL-2,
platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and
transforming growth factor alpha (TGF alpha), failed to stimulate either
GM-CSF or G-CSF production, whether alone or in the presence of IL-1. These
results suggest that cytokine-stimulated synovial fibroblasts may be a
major source of intraarticular CSF production in the joints of patients
with inflammatory arthritis; as a result, monocyte/macrophages and
granulocytes may be activated, leading to perpetuation of the inflammation
and destructive events occurring in these lesions.
Volume 76,
Issue 10,
pp. 1989-1996,
11/15/1990
Copyright © 1990 by The American Society of Hematology
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