Endogenous neutralization of TGF-β and IL-6 ameliorates septic arthritis by altering RANKL/OPG interaction in...

Septic arthritis is an inflammatory joint disease caused by S. aureus. Hematogenous entry of the bacteria to the synovium produces pro-inflammatory cytokines TGF-β and IL-6, which alter the Th17/Treg balance. Hence, targeting TGF-β and IL-6 could be beneficial in ameliorating arthritis. Antibody neutralization of TGF-β and IL-6 to modulate Th17/Treg homeostasis and RANKL/OPG ratio are not investigated so far in S. aureus-induced septic arthritis. Contribution of synovial lymphocyte-derived cytokines IL-10, IL-12, and CXCL-8; along with OPN, OPG, CRP, cellular ROS, antioxidant enzymes, and the expressions of RANKL, SAPK-JNK, MMP2, SOD, CAT, GP_x, TGF-β and IL-6 were studied in lymphocytes of blood, spleen and synovial tissues of mice treated with antibody against of TGF-β and IL-6 after induction of septic arthritis. Dual neutralization of TGF-β and IL-6 is effective in shifting the Th17 cell into immunosuppressive Treg cell of the arthritic mice and enhances the RANKL/OPG interaction leading to the down-regulation of osteoclastic activity and reduces the production of OPN, IL-12, CXCL-8, and CRP. Additionally, it reduces oxidative stress via enhancing the activities of antioxidant enzymes including SOD, catalase, and GP_x in lymphocytes. Thus it can be concluded that dual endogenous neutralization of TGF-β and IL-6 may be chosen as an alternative therapeutic approach for controlling the severity of septic arthritis through Treg-derived IL-10 that could ameliorate the inflammatory consequences of septic arthritis via influencing RANKL/OPG interaction in lymphocytes.