Mechanism of Mir-218-5P in Autophagy, Apoptosis and Oxidative Stress in Rheumatoid Arthritis Synovial Fibroblasts is Mediated by Klf9 and Jak/Stat3 Pathways

Abstract

This study was aimed to investigate the effects of miR-218-5p on the proliferation, apoptosis, autophagy, and oxidative stress of rheumatoid arthritis synovial fibroblasts (RASFs), and the related mechanisms. Quantitative reverse transcription–PCR showed that the expression of miR-218-5p in rheumatoid arthritis synovial tissue was significantly higher than that in healthy synovial tissue. Compared with healthy synovial fibroblasts, miR-218-5p expression was obviously upregulated in RASFs, while KLF9 protein expression was markedly downregulated. Mechanistically, miR-218-5p could directly bind to the 3′ untranslated region of KLF9 to inhibit the expression of KLF9. Additionally, transfection of miR-218-5p small interfering RNA (siRNA) inhibited the proliferation but promoted apoptosis and autophagy of RASFs. Simultaneously, miR-218-5p silencing reduced reactive oxygen species and malondialdehyde levels and increased superoxide dismutase and glutathione peroxidase activity to improve oxidative stress in RASFs. More importantly, the introduction of KLF9 siRNA reversed the effects of miR-218-5p siRNA transfection on RASF proliferation, apoptosis, autophagy, and oxidative stress. What is more, silencing miR-218-5p inhibited the activation of JAK2/STAT3 signaling pathway by targeting KLF9. Collectively, knockdown of miR-218-5p could regulate the proliferation, apoptosis, autophagy and oxidative stress of RASFs by increasing the expression of KLF9 and inhibiting the activation of the JAK2/STAT3 signaling pathway, which may provide a potential target for the mechanism research of RA.

Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

“…TYK2 also mediates the signalling of IL-6, IL-10 and IL-4/IL-13 36. IL-6 signals through the IL-6 receptor (IL-6R), thereby inducing IL6ST homodimerisation and activation of TYK2/JAK1/2 and STAT3 signalling pathway (figure 4), known to play a role in RA 37. The intronic variant rs7731626-A in ANKRD55 associated with a reduced risk of both seropositive and seronegative RA and also reduced expression of ANKRD55 and IL6ST .…”

“… 36 IL-6 signals through the IL-6 receptor (IL-6R), thereby inducing IL6ST homodimerisation and activation of TYK2/JAK1/2 and STAT3 signalling pathway ( figure 4 ), known to play a role in RA. 37 The intronic variant rs7731626-A in ANKRD55 associated with a reduced risk of both seropositive and seronegative RA and also reduced expression of ANKRD55 and IL6ST . The effect on IL6ST expression and its biological function points to IL6ST as a candidate causal gene at that locus.…”

HPV8 Reverses the Transcriptional Output in Lrig1 Positive Cells to Drive Skin Tumorigenesis

“…Recently, it was shown that constitutively active STAT3 signalling significantly changes the behaviour of keratinocyte stem/progenitor cells residing in the hair follicle [ 45 ], and that disruption of STAT3 in keratinocytes compromises wound-healing and affects initiation and promotion of skin tumours [ 46 , 47 ]. STAT3 signalling is known to regulate miRNAs and to be regulated by miRNAs including miR-155-5p, miR-181b-5p and miR-218-5p [ 48 , 49 ]. Interestingly, SPI1, ETS1 and CEBP/beta are all known targets of miR-155 [ 50 , 51 ], with miR-155 mechanistically inhibiting PU.1 expression.…”

KLF9 positively regulates TRIM33 to inhibit abnormal synovial fibroblast proliferation, migration as well as inflammation in rheumatoid arthritis

“…KLF9 upregulation inhibited tumor necrosis factor‐α (TNF‐α)‐evoked human FLS migration, proliferation as well as inflammation 11 . KLF9 protein expression was significantly downregulated in RA synovial fibroblasts (RASF) relative to healthy synovial fibroblasts, and elevated KLF9 expression suppressed RA development 12 …”

“…11 KLF9 protein expression was significantly downregulated in RA synovial fibroblasts (RASF) relative to healthy synovial fibroblasts, and elevated KLF9 expression suppressed RA development. 12 Therefore, we hypothesized that KLF9 positively regulated the transcription of TRIM33, which inhibited RA progression.…”