Blocking of YY1 reduce neutrophil infiltration by inhibiting IL‐8 production via the PI3K‐Akt‐mTOR signaling pathway in rheumatoid arthritis

Summary Our previous study revealed that Yin Yang 1(YY1) played an important part in promoting interleukin (IL)‐6 production in rheumatoid arthritis (RA). However, whether YY1 has any role in regulation of IL‐8 in RA remains unclear. YY1 and IL‐8 expression in RA patients were analyzed by real‐time polymerase chain reaction (PCR). Ingenuity pathway analysis (IPA) was used to analyze the signaling pathway involved in YY1‐induced IL‐8 production. The expression of YY1 and proteins involved in the pathway were detected by Western blot and enzyme‐linked immunosorbent assay (ELISA). Migration of neutrophils was performed by chemotaxis assay. In this study, we found that high expression of IL‐8 was positively associated with YY1 expression in RA. Blocking YY1 expression by YY1‐short hairpin (sh)RNA lentivirus reduced IL‐8 production. Mechanistically, we showed YY1 activated IL‐8 production via the phosphatidylinositol‐3‐kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway. Further, using a co‐culture system consisting of peripheral blood mononuclear cells (PBMC) and neutrophils, we found that migration of neutrophils would be inhibited by YY1 RNA interference. Finally, using the collagen‐induced arthritis animal model, we showed that treatment with the YY1‐shRNA lentivirus led to reduction of IL‐8 levels and attenuation of inflammation and neutrophil infiltration in vivo . Our results reveal a role of YY1 involved in neutrophil infiltration in RA via the PI3K/Akt/mTOR/IL‐8 signaling pathway. YY1 may be a new therapeutic target for treatment of RA.