Synergistic effect of Bruton's tyrosine kinase and TNF-α in the regulation of rheumatoid arthritis and underlying mechanisms.

Abstract

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.