Ellipticine Blocks Synergistic Effects Of IL-17A And TNF-α In Epithelial Cells And Alleviates Severe Acute Pancreatitis-associated Acute Lung Injury

IL-17 A combined with TNF-α plays a vital role in inflammatory response and interference of the synergistic effect is an effective strategy for treating inflammatory diseases.Ellipticine,a natural alkaloid,has biological activities on anti-tumor and anti-HIV.However,it is still unknown whether ellipticine can inhibit IL-17 A and TNF-α-mediated signaling and has treatment effect on PALI.Here,we reported that ellipticine significantly inhibited the production of pro-inflammatory cytokines and chemokines in pulmonary epithelial cell BEAS-2B treated with IL-17 A and TNF-α,but not IL-17 A or TNF-α alone.Meanwhile,ellipticine attenuated NF-kB and MAPKs activation in response to IL-17 A and TNF-α treatment,inhibited Act1 and TRAF6-mediated NF-kB activation,and blocked the interaction of Act1 with TRAF6.Furthermore,we found that ellipticine significantly alleviated CAE and LPS-induced SAP/PALI.Ellipticine treatment dramatically reduced inflammatory cells infiltration,MPO activity,serum amylase and lipase activity and the protein concentration of BALF.Collectively,our findings indicate that ellipticine inhibits the synergistic effect of IL-17 A and TNF-α by targeting on Act1 and TRAF6 interaction and is a potential therapeutic agent for the treatment of SAP/PALI.