Specialized Pro-Resolving Mediators Do Not Inhibit the Synthesis of Inflammatory Mediators Induced by Tumor Necrosis Factor-α in Synovial Fibroblasts

Abstract

Background Tumor necrosis factor (TNF)-α, a proinflammatory cytokine, is involved in the pathogenesis of rheumatoid arthritis (RA). The omega-3 unsaturated fatty acid-derived metabolites resolvin (Rv) D1, RvE1, and maresin-1 (MaR1) have been reported as anti-inflammatory lipid mediators and are known as specialized pro-resolving mediators (SPMs). In this study, we aimed to investigate the anti-inflammatory effects of SPMs on TNF-α-induced responses in synovial fibroblasts. Methods We investigated the effects of SPMs on gene expression and/or production of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), interleukin (IL)-6, and matrix metalloproteinase (MMP)-3, which are involved in TNF-αinduced synovitis in RA or OA synovial fibroblasts, by quantitative real-time PCR. We also investigated the effects of SPMs on the mitogen-activated protein kinase (MAPK) signaling pathway by western blotting. Antiinflammatory effects of SPMs were evaluated by applying SPMs to cultured synovial fibroblasts, followed by TNF-α stimulation. Results The induction of COX-2, mPGES-1, IL-6, and MMP-3 by TNF-α in synovial fibroblasts was not suppressed by omega 3-derived SPMs regardless of their origin such as RA or OA. SPMs had no effect on lipid mediator receptor gene expression induce by TNF-α and did not inhibit the TNF-α-activated MAPK signaling pathway. The production of COX-2 and IL-6 protein was significantly decreased by p38 inhibitor. Conclusion Despite reports on the anti-inflammatory effect of omega 3-derived SPMs, its anti-inflammatory effect on TNF-α-induced responses was not observed in synovial fibroblasts. The reason may be that SPMs have no suppressive effect on p38 activation, which plays an important role in the production of inflammatory cytokines in synovial fibroblasts.

Saturated fatty acids negatively affect musculoskeletal tissues in vitro and in vivo

“…This finding is consistent with Ezure and Amano who saw no difference in either cell abundance or ColIa1 expression compared to control as a function of EPA [31] . These data suggest that even though EPA may have anti-inflammatory effects in the cardiovascular system [32] , [33] , [34] and in patients with cancer [35] , the effect of EPA on the musculoskeletal system is less clear [36] , [37] .…”

Targeting the Inflammatory Hallmarks of Obesity-Associated Osteoarthritis: Towards Nutraceutical-Oriented Preventive and Complementary Therapeutic Strategies Based on n-3 Polyunsaturated Fatty Acids

“…Indeed, EPA and DHA, incorporated on synovial membranes, counteracted IL-β-induced inflammation by generating several pro-resolving docosanoids (RvD1, RvD2, Mar and PDX) [108]. However, in another study, similar SPMs (RvD1, RvE1 and MaR1) were not able to modulate inflammatory and catabolic markers induced by stimulation with TNF-α [122]. The elucidation of the molecular mechanisms implicated in the protective effects of n-3 PUFAs on inflammatory synoviocytes comes from two preclinical in vitro studies that identified the activation of Hippo-YAP [123] and the inhibition of the NF-κB p65 pathway [124].…”