Advanced oxidation protein products induce inflammatory responses and invasive behaviour in fibroblast-like synoviocytes via the RAGE-NF-κB pathway

Aims Rheumatoid arthritis (RA), which mainly results from fibroblast-like synoviocyte (FLS) dysfunction, is related to oxidative stress. Advanced oxidation protein products (AOPPs), which are proinflammatory mediators and a novel biomarker of oxidative stress, have been observed to accumulate significantly in the serum of RA patients. Here, we present the first investigation of the effects of AOPPs on RA-FLSs and the signalling pathway involved in AOPP-induced inflammatory responses and invasive behaviour. Methods We used different concentrations of AOPPs (50 to 200 mu g/ml) to treat RA-FLSs. Cell migration and invasion and the expression levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), and MMP-13 were investigated. Western blot and immunofluorescence were used to analyze nuclear factor-kappa B (NF-kappa B) activation. Results AOPPs promoted RA-FLS migration and invasion in vitro and significantly induced the messenger RNA (mRNA) and protein expression of TNF-alpha, IL-6, MMP-3, and MMP-13 in dose- and time-dependent manners. Moreover, AOPPs markedly activated the phosphorylation of nuclear factor-kappa B (NF-kappa B) p65 protein, which triggered inhibitory kappa B-alpha (I kappa B alpha) degradation, NF-kappa B p65 protein phosphorylation, and NF-kappa B p65 translocation into the nucleus. Furthermore, treatment with a neutralizing antibody specific to receptor for advanced glycation end products (RAGE) significantly suppressed aggressive behaviour and inflammation, decreased TNF-alpha, IL-6, MMP-3, and MMP-13 expression, and blocked AOPP-induced NF-kappa B pathway activation. Conclusion The results indicate that AOPPs can enhance aggressive behaviour and the inflammatory response in RA-FLSs via the RAGE-NF-kappa B pathway. These results present AOPPs as a new class of potentially important mediators of progressive disease in RA patients.

Automated summary

AOPPs can enhance aggressive behavior and the inflammatory response in RA-FLSs via the RAGE-NF-kappa B pathway, presenting them as potential important mediators of progressive disease in RA patients.