Paeoniflorin induced immune tolerance of mesenteric lymph node lymphocytes via enhancing beta 2-adrenergic receptor desensitization in rats with adjuvant arthritis

Paeoniflorin (Pae), a monoterpene glucoside, is one of the main bioactive components of total glucosides of paeony (TGP) extracted from the root of Paeonia lactiflora. TGP has anti-inflammatory and immunoregulatory effects. In this study, we investigated the effects of Pae on inflammatory and immune responses to the mesenteric lymph node (MLN) lymphocytes and the mechanisms by which Pae regulates beta 2-adrenergic receptor (beta 2-AR) signal transduction in adjuvant arthritis (AA) rats. The onset of secondary arthritis in rats appeared around day 14 after injection of Freund's complete adjuvant (FCA). Remarkable secondary inflammatory response and lymphocytes proliferation were observed in AA rats, along with the decrease of anti-inflammatory cytokines interleukin (IL)-4 and transforming growth factor-beta 1 (TGF-beta 1) of MLN lymphocytes, and the increase of pro-inflammatory cytokine IL-2. The administration of Pae (50, 100 mg kg−1, days 17–24) significantly diminished the secondary hind paw swelling and arthritis scores, reversed the changes of cytokines as discussed above, and further decreased the lowered proliferation of MLN lymphocytes in AA rats. In vitro, Pae restored the previously increased level of cAMP of MLN lymphocytes at the concentrations of 12.5, 62.5 and 312.5 mg l−1. Meanwhile, Pae increased protein expressions of beta 2-AR and GRK2, and decreased that of beta-arrestin 1, 2 of MLN lymphocytes in AA rats. These results suggested that Pae might induce the Th1 cells immune tolerance, which then shift to Th2, Th3 cells mediated activities to take effect the anti-inflammatory and immunoregulatory effects. The mechanisms of Pae on beta 2-AR desensitization and beta 2-AR-AC-cAMP transmembrane signal transduction of MLN lymphocytes play crucial roles in pathogenesis of this disease.