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.
Leizer
T
T
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia.
Cebon
J
J
Layton
J E
JE
Hamilton
J A
JA
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