Dihydroarteannuin Ameliorates Collagen-Induced Arthritis Via Inhibiting B Cell Activation by Activating the Fc gamma RIIb/Lyn/SHP-1 Pathway

Background: Dihydroarteannuin (DHA), which is extracted from the traditional Chinese herb Artemisia annua L, exhibits potent immunosuppressive activity in rheumatoid arthritis (RA). Strong evidence indicates that B cells act as an essential factor in the pathogenesis of RA, but research on the immunosuppressive function of DHA in regulating B cells is limited.& nbsp;Objective: To investigate the modulatory effects of DHA on joint destruction, proinflammatory cytokine production, activation, apoptosis and proliferation of B cells and to explore the possible associated mechanism in RA treatment.& nbsp;Methods: Collagen-induced arthritis (CIA) model was established. Weight and joint oedema were record weekly, and joint damage was detected by micro-CT scan. Human Burkitt B lymphoma cells lacking endogenous Fc gamma receptor b (Fc gamma RIIb) gene were transfected with a 232Thr loss-of-function mutant to construct a mutant cell model ST486. The proliferation of ST486 cells was assessed with Cell Counting Kit-8. Apoptosis and activation were tested by flow cytometry. The effects of DHA on the activation of Fc gamma RIIb, protein tyrosine kinases (Lyn), and SH2-containing tyrosine phosphatase-1 (SHP-1) signaling pathways were determined by western blotting.& nbsp;Results: In comparison to model group, bone volume/tissue volume (BV/TV) and bone mineral density (BMD) were increased, whereas joint oedema was decreased in both of the DHA and MTX group. The mRNA and protein expression levels of Interleukin-6 (IL-6) and Tumor necrosis factor-alpha (TNF-alpha) were decreased after treatment with DHA. In addition, DHA treatment promoted the apoptosis, inhibited the activation and proliferation of ST486 cells. Furthermore, the protein expression levels of Fc gamma RIIb, SHP-1, and Lyn were increased after treatment with DHA. Moreover, the expression of phosphorylated CD19 was also inhibited by DHA.& nbsp;Conclusion: We provide the first evidence that DHA may alleviate collagen-induced arthritis by activating the Fc gamma RIIb/Lyn/SHP-1 signaling pathway in B cell, indicating that DHA is a novel and valuable candidate for RA therapy.