Background Mycophenolic acid (MPA) has been used for many years to prevent transplantation rejection. Recently, it has been investigated for its anti-inflammatory effects. MPA can be beneficial in the prevention or treatment of atherosclerosis, playing a crucial role in preventing cardiovascular disease in organ transplant recipients. This study was conducted to evaluate the exactmechanism of anti-inflammatory action by MPA, including the involvement of toll-like receptor 4 (TLR4) and tumor necrosis factor 1 (TNFR1), two proteins that reside on the surface of the cell membrane and initiate inflammatory signaling.

Methods The MPA-induced anti-inflammatory pathway was evaluated by siRNA transfection, immunoprecipitation, and western blot using in vitro cultures of human aortic endothelial cells.

Results MPA was found to induce the ectodomain shedding of TLR4 and TNFR1, an effect that was not observed in Ca²⁺-free medium. Further downstream in the pathway, MPA inhibited TNF-α-induced activation of spleen tyrosine kinase (Syk), p38 mitogen-activated protein kinase (p38 MAPK), mitogen- and stress-activated protein kinase 1 (MSK1), and NF-κB p65 (p65). Depletion of Syk inhibited TNF-α-induced MSK1 activation. MPA had an inhibitory effect on nuclear p65 binding, which was mediated by inhibition of MSK1 without any effect on the nuclear translocation of p65 or the cytoplasmic degradation of IκBα.

Conclusion MPA has an anti-inflammatory effect on the initiation of inflammation through the Ca²⁺-dependent shedding of TNFR1 and TLR4 and, subsequently, through inhibition of downstream intracellular inflammatory cascades.

CITATION INFORMATION: Kim J, Yang W, Baek C, Han N, Park S.-K. Mycophenolic Acid Needs Ca²⁺ to Exert Its Anti-inflammatory Action via Shedding of Toll-Like Receptor4 and Tumor Necrosis Factor Receptor 1. Am J Transplant. 2017;17 (suppl 3).

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