Abstract
BackgroundThe inflammatory cascade in the rheumatoid arthritis (RA) synovium is modulated by a variety of cytokine and chemokine networks; however, the roles of IL-26, in RA pathogenesis, are poorly defined. Here, we investigated the functional role of interleukin-26 (IL)-26 in osteoclastogenesis in RA.MethodsWe analyzed levels of IL-20 receptor subunit A (IL-20RA), CD55, and receptor activator of nuclear factor kappaB (NF-κB) ligand (RANKL) in RA fibroblast-like synoviocytes (FLSs) using confocal microscopy. Recombinant human IL-26-induced RANKL expression in RA-FLSs was examined using real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Human peripheral blood monocytes were cultured with macrophage colony-stimulating factor (M-CSF) and IL-26, after which osteoclastogenesis was evaluated by counting the number of tartrate-resistant acid phosphatase-positive multinucleated cells. Additionally, osteoclastogenesis was evaluated by monocytes co-cultured with IL-26-prestimulated FLSs.ResultsThe expression of IL-20RA in RA-FLSs was higher than that in osteoarthritis-FLSs. Additionally, in IL-26-pretreated RA-FLSs, the expression of IL-20RA (but not IL-10 receptor subunit B) and RANKL increased in a dose-dependent manner, with IL-26-induced RANKL expression reduced by IL-20RA knockdown. Moreover, IL-26-induced RANKL expression was significantly downregulated by inhibition of signal transducer and activator of transcription 1, mitogen-activated protein kinase, and NF-κB signaling. Furthermore, IL-26 promoted osteoclast differentiation from peripheral blood monocytes in the presence of low dose of RANKL, with IL-26 exerting an additive effect. Furthermore, co-culture of IL-26-pretreated RA-FLSs with peripheral blood monocytes also increased osteoclast differentiation in the absence of addition of RANKL.ConclusionsIL-26 regulated osteoclastogenesis in RA through increased RANKL expression in FLSs and direct stimulation of osteoclast differentiation. These results suggest the IL-26/IL-20RA/RANKL axis as a potential therapeutic target for addressing RA-related joint damage.
Highlights
The inflammatory cascade in the rheumatoid arthritis (RA) synovium is modulated by a variety of cytokine and chemokine networks; the roles of IL-26, in RA pathogenesis, are poorly defined
IL-20 receptor subunit A (IL-20RA) and RANKL levels in RA-Fibroblast-like synoviocyte (FLS) To investigate the expression of IL-20RA and RANKL in RA and OA-FLS, we investigated their levels by confocal microscopy with multiple-fluorescence staining
We found that IL-20RA, RANKL, and CD55 were abundantly expressed in RA-FLSs but negligibly expressed in OA-FLSs and that dual-immunofluorescent labeling of IL-20RA and RANKL revealed consistent overlaps between RANKL, IL-20RA, and CD55 (Fig. 1a–c)
Summary
The inflammatory cascade in the rheumatoid arthritis (RA) synovium is modulated by a variety of cytokine and chemokine networks; the roles of IL-26, in RA pathogenesis, are poorly defined. Th17 cells are a distinct lineage of CD4+ Th cells characterized by the production of a variety of proinflammatory cytokines, Lee et al Arthritis Research & Therapy (2019) 21:283 including interleukin (IL)-17A, IL-17F, IL-6, IL-21, IL-22, IL-26, tumor necrosis factor (TNF)-α, and granulocytemacrophage colony-stimulating factor [4]. Considerable evidence from both animal models and humans shows that IL-17 is involved in inflammatory cascades and in joint damage through its activation of osteoclast differentiation (i.e., osteoclastogenesis) [4,5,6]. IL-22 binds receptor complexes containing IL-10RB/IL-22RA1, whereas IL-19, IL-20, and IL-24 bind the heterodimer receptor complex comprising IL-20RA/IL20RB [12]
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