FJU-C28 inhibits the endotoxin-induced pro-inflammatory cytokines expression via suppressing JNK, p38 MAPK and NF-κB signaling pathways

Abstract

Despite marked improvements in supportive care, the mortality rate of acute respiratory distress syndrome due to the excessive inflammatory response caused by direct or indirect lung injury induced by viral or bacterial infection is still high. In this study, we explored the anti-inflammatory effect of FJU-C28, a new 2-pyridone-based synthetic compound, on lipopolysaccharide (LPS)-induced inflammation in vitro and in vivo models. FJU-C28 suppressed the LPS-induced mRNA and protein expression of iNOS, COX2 and proinflammatory cytokines. The cytokine protein array results showed that LPS stimulation enhanced the secretion of IL-10, IL-6, GCSF, Eotaxin, TNFα, IL-17, IL-1β, Leptin, sTNF RII, and RANTES. Conversely, the LPS-induced secretion of RANTES, TIMP1, IL-6, and IL-10 was dramatically suppressed by FJU-C28. FJU-C28 suppressed the LPS-induced expression of RANTES, but its parental compound FJU-C4 was unable to diminish RANTES in cell culture media or cell lysates. FJU-C28 blocked the secretion of IL-6 and RANTES in LPS-activated macrophages by regulating the activation of JNK, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB). FJU-C28 prevented the LPS-induced decreases in lung function including vital capacity (VC), lung compliance (C chord), forced expiratory volume at 100 ms (FEV100), and forced vital capacity (FVC) in mice with LPS-induced systemic inflammatory responses. FJU-C28 also reduced neutrophil infiltration in the interstitium, lung damage and circulating levels of IL-6 and RANTES in mice with systemic inflammation. In conclusion, these findings suggest that FJU-C28 possesses anti-inflammatory activities to prevent endotoxin-induced lung function decrease and lung damages by down-regulating proinflammatory cytokines including IL-6 and RANTES via suppressing the JNK, p38 MAPK and NF-κB signaling pathways.