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.
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.
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia.
T
T
Leizer
J
J
Cebon
J E
JE
Layton
J A
JA
Hamilton
D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000502:physiology*; D007376:Interleukin-2 / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D015846:Monokines / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D013583:Synovial Membrane / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D007375:Interleukin-1; D007376:Interleukin-2; D007377:Interleukin-3; D015846:Monokines; D010982:Platelet-Derived Growth Factor; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D003609:Dactinomycin; D004815:Epidermal Growth Factor; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003513:Cycloheximide