Abstract
The inflammatory cytokine interleukin-26 (IL-26) is highly expressed in the serum and synovial fluid of patients with inflammatory arthritis. The effect of IL-26 on human articular chondrocytes (HACs) remains unclear. Obesity is associated with disability of patients with rheumatoid arthritis and disease activity in those with ankylosing spondylitis. The saturated free fatty acid palmitate with IL-1β can synergistically induce catabolic effects in HACs. The aim of this study was to evaluate the effects of IL-26 and palmitate in HACs. In this study, palmitate markedly synergizes the IL-26-induced proinflammatory effects and matrix protease, including COX-2, IL-6, and MMP-1, in HACs via the toll-like receptor 4 (TLR4)-ERK1/2-c-Jun signal transduction pathway. The synergistic catabolic effects of palmitate and IL-26 were attenuated by inhibitors of TLR4 (TAK242), ERK1/2 (U0126), or c-Jun (SP600125) in HACs and cartilage matrix. In addition, metformin, a potential inhibitor of TLR4, also decreased expression of COX-2 and IL-6 induced by co-incubation with IL-26 and palmitate. IL-26 and palmitate synergistically induced expression of inflammatory and catabolic mediators, resulting in articular cartilage matrix breakdown. The present study also revealed a possible mechanism and therapeutic targets against articular cartilage degradation by increased saturated fatty acids in patients with inflammatory arthritis.
Highlights
Interleukin-26 (IL-26) is a proinflammatory cytokine, initially identified in herpesvirustransformed T cells in 2000 [1], that can induce the production of other proinflammatory cytokines via activation of its heterodimer receptor, a complex of IL-10 receptor 2 and IL-20 receptor 1, through phosphorylation of signal transducers and activators of transcription (STAT)-1/3 and extracellular signal-regulated protein kinases (ERK)-1/2 [2]
This is the first report of the proinflammatory effects of IL-26 on articular cartilage and synergistic action with palmitate to promote the Inflammatory arthritis is associated with high serum and synovial fluid levels of IL-26, obesity, and disease activity [13,14]
This is the first report of the proinflammatory effects of IL-26 on articular cartilage and synergistic action with palmitate to promote the breakdown of the cartilage matrix
Summary
Interleukin-26 (IL-26) is a proinflammatory cytokine, initially identified in herpesvirustransformed T cells in 2000 [1], that can induce the production of other proinflammatory cytokines via activation of its heterodimer receptor, a complex of IL-10 receptor 2 and IL-20 receptor 1, through phosphorylation of signal transducers and activators of transcription (STAT)-1/3 and extracellular signal-regulated protein kinases (ERK)-1/2 [2]. Saturated FFAs can induce cytokine production via activation of toll-like receptor (TLR) 2/4 through mitogen-activated protein kinase (MAPK) and the nuclear factor (NF)-κB or AP-1 signaling pathway [9,10,11]. A previous study reported that the saturated FFA palmitate (C16:0), but not monounsaturated oleate (C18:1), has synergistic catabolic effects with IL-1β in HACs [12]. High rates of obesity are associated with disability of patients with rheumatoid arthritis and disease activity of ankylosing spondylitis [13,14]. The association of IL-26 and saturated FFAs in HACs has not been investigated. The aim of the present study was to evaluate the synergistic effects of palmitate and IL-26 in HACs
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