Interferon-gamma enhances interleukin 12 production in rheumatoid synovial cells via CD40-CD154 dependent and independent pathways.
OBJECTIVE
To determine the role of interferon-gamma (IFN-gamma) in CD40-CD154 dependent production of interleukin 12 (IL-12) by synovial cells of patients with rheumatoid arthritis (RA).


METHODS
We examined the effects of IFN-gamma, tumor necrosis factor-alpha (TNF-alpha), and granulocyte-macrophage colony stimulating factor (GM-CSF) on CD40 expression on CD68+ synovial macrophage-lineage cells (SMC). The effects of IFN-gamma and soluble CD154 (sCD154) on IL-12 production by RA synovial cells were determined by ELISA.


RESULTS
CD68+ SMC expressed substantial levels of CD40. IFN-gamma, but not TNF-alpha or GM-CSF, markedly upregulated CD40 expression on CD68+ SMC. IFN-gamma also dose dependently increased IL-12 production by synovial cells. The effects of IFN-gamma on CD40 expression (EC50 = 127.4 U/ml) were observed at a concentration 19 times lower than the effects on IL-12 production (EC50 = 6.8 U/ml). Treatment with IFN-gamma at a concentration low enough to augment CD40 expression but not IL-12 production enhanced spontaneous IL-12 production synergy with sCD 154. The synergistic enhancement of spontaneous IL-12 production was abrogated by CD40-Fc. In contrast, IL-12 production induced by high concentration of IFN-gamma was not neutralized by CD40-Fc.


CONCLUSIONS
IFN-gamma enhanced IL-12 production via both CD40-CD154 dependent and independent pathways in RA synovium. IFN-gamma may play a crucial role in the development of RA synovitis through regulation of IL-12 production.
Kitagawa
M
M
Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.
Suzuki
H
H
Adachi
Y
Y
Nakamura
H
H
Yoshino
S
S
Sumida
T
T
D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism* / Q000494:pharmacology; D019070:Cell Lineage / Q000276:immunology; D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D018664:Interleukin-12 / Q000096:biosynthesis*; D008264:Macrophages / Q000737:chemistry / Q000166:cytology; D012995:Solubility; D013583:Synovial Membrane / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D023201:CD40 Ligand; D007371:Interferon-gamma; D018664:Interleukin-12; C067980:CD68 antigen, human; D000097382:CD68 Molecule