Synergistic effect of Bruton's tyrosine kinase and TNF‑α in the regulation of rheumatoid arthritis and underlying mechanisms
Affiliations: Department of Rheumatology and Immunology, Chongqing Ninth People's Hospital, Beibei, Chongqing 400700, P.R. China
- Published online on: December 14, 2021 https://doi.org/10.3892/etm.2021.11064
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The presence of Bruton's tyrosine kinase (BTK) in macrophages has been recommended as a promising therapeutic target for rheumatoid arthritis (RA). In addition, activated macrophages in the inflamed joints of patients with RA can also produce a plethora of cytokines, such as TNF‑α. The aim of the present study was to investigate the potential role of BTK and TNF‑α in the regulation of RA. The results demonstrated that higher levels of BTK and TNF‑α were observed in macrophages in inflamed RA joints compared with those in normal joint tissues. Subsequently, the role of BTK and TNF‑α in the regulation of cellular process in inflammatory macrophages was analyzed. It was demonstrated that aberrant expression of BTK and TNF‑α in inflammatory macrophages can lead to higher cell proliferation rates. Once the expression of BTK or TNF‑α was restricted by using short interfering (si)RNAs (siBTK or siTNF‑α), the activity of inflammatory macrophages was significantly downregulated. Of note, when the expression of BTK and TNF‑α was simultaneously decreased, the proliferation rate of inflammatory macrophages was inhibited to the greatest extent. Subsequently, the underlying mechanisms through which BTK and TNF‑α can regulate RA were investigated. The results demonstrated that BTK mainly regulated the ERK/JNK pathway, while TNF‑α mainly affected the inactive rhomboid protein 2/B‑cell‑activating factor pathway. Finally, animal experiments demonstrated that simultaneous silencing of both BTK and TNF‑α can significantly alleviate the symptoms associated with RA.