ABSTRACT
BACKGROUND: Interleukin (IL)-34 is a new pro-inflammatory cytokine. Previous studies showed that IL-34 plays a key role in inflammation and osteoporosis in rheumatoid arthritis (RA). However, whether IL-34 participates in angiogenesis in RA remains unknown. Vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) play critical roles in the angiogenesis of RA. METHODS: 22 patients with RA, 18 patients with ankylosing spondylitis (AS), and 8 healthy subjects were enrolled in this study. Peripheral blood mononuclear cells (PBMCs) were isolated and purified from peripheral blood by density gradient centrifugation. PBMCs were stimulated using anti-CD3/CD28 antibody and different concentrations of recombinant human (rh) IL-34 (0, 10, 20, 50, 100 ng/mL). Cell-free supernatants were collected after 72 h incubation, and VEGF and HIF-1α levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: IL-34 promotes the secretion of VEGF and HIF-1α by PBMCs in RA patients in a dose-dependent manner. In contrast, IL-34 has no effect on VEGF and HIF-1α secretion by PBMCs in AS and healthy controls. CONCLUSION: IL-34 may indirectly contribute to angiogenesis by promoting the production of VEGF and HIF-1α and participate in the pathogenesis of RA.
Subject(s)
Arthritis, Rheumatoid/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis , Interleukins/metabolism , Leukocytes, Mononuclear/metabolism , Vascular Endothelial Growth Factor A/biosynthesis , Aged , Cells, Cultured , Female , Humans , Male , Middle Aged , Neovascularization, Pathologic/metabolismABSTRACT
OBJECTIVE: To detect the effect of interleukin (IL)-34 on the secretion of Receptor activator of nuclear factor kappa-B ligand (RANKL)/Osteoprotegerin (OPG) and Matrix metalloproteinase (MMP)-3 by fibroblast-like synoviocytes (FLS) and peripheral blood mononuclear cells (PBMCs) of rheumatoid arthritis (RA) patients and to investigate whether the effect is mediated by IL-17. METHOD: RA-FLS and RA-PBMCs were stimulated with recombinant human (rh) IL-34, with or without the IL-17 inhibitor Plumbagin. The supernatant of the culture medium was collected and the levels of RANKL, OPG, and MMP-3 were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: RhIL-34 promoted RANKL secretion and inhibited OPG secretion in RA-FLS. The effect was weakened by the addition of the IL-17 inhibitor. In contrast, rhIL-34 had no significant effect on MMP-3 secretion by FLS. RhIL-34 elevated the secretion of RANKL by RA-PBMCs but not by healthy-PBMCs. Furthermore, the secretion of RANKL by RA-PBMCs reduced after the addition of the IL-17 inhibitor. OPG secretion by both RA-FLS and FLS from healthy controls was inhibited by rhIL-34, but were elevated after the addition of the IL-17 inhibitor. RhIL-34 had no significant effect on MMP-3 secretion by both RA-PBMCs and healthy-PBMCs. CONCLUSION: IL-34 enhances RANKL/OPG expression by RA-FLS and RA-PBMCs, and this effect is, indirectly, mediated by IL-17. This cytokine is therefore likely to to play an important role in local joint destruction and systemic osteoporosis in RA, and is therefore a potential therapeutic target for the treatment of this disease.
