Tussilagone Inhibits the Inflammatory Response and Improves Survival in CLP-Induced Septic Mice

Abstract

Tussilagone, extracted from Tussilago farfara is an oriental medicine used for asthma and bronchitis. We investigated its mechanism of action, its inhibitory effects on lipopolysaccharide-induced inflammation in macrophages, and its impact on viability in a cecal ligation and puncture (CLP)-induced mouse model of sepsis. Tussilagone suppressed the expression of the inflammatory mediators, nitric oxide and prostaglandin E2, and the inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and high-mobility group box 1 (HMGB1), in lipopolysaccharide-stimulated RAW 264.7 cells and peritoneal macrophages. Tussilagone also reduced the activation of the mitogen-activated protein kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) involved in the activation of various inflammatory mediators in activated macrophages. Moreover, tussilagone administration (1 mg/kg and 10 mg/kg) produced decreased mortality and lung injury in CLP-activated septic mice. Augmented expression of cyclooxygenase (COX)-2 and TNF-α in pulmonary alveolar macrophages of septic mice were attenuated by tussilagone administration. Tussilagone also suppressed the induction of nitric oxide, prostaglandin E2, TNF-α and HMGB1 in the serum of the septic mice. Overall, tussilagone exhibited protective effects against inflammation and polymicrobial sepsis by suppressing inflammatory mediators possibly via the inhibition of NF-κB activation and the MAP kinase pathway. These results suggest the possible use of tussilagone for developing novel therapeutic modalities for sepsis and other inflammatory diseases.

Tussilagone Inhibits Osteoclastogenesis and Periprosthetic Osteolysis by Suppressing the NF-κB and P38 MAPK Signaling Pathways

“…Comparatively, most previous studies have suggested that TUS suppresses the activation of NF-kB pathway, while the modulated targets vary. Cheon et al (2018), Choi et al (2018), Hwang et al (2018), Kim et al (2017b), Lee et al (2016) and Lim et al (2008) all have reported that TUS blocks NF-kB pathway in exogenous-agent-induced colitis mice, airway epithelial cells, focal cerebral ischemia rats, septic mice, skin inflammation mice, and BV-2 microglial cells by attenuating the nuclear translocation of p65 subunit and the phosphorylation and (or) degradation of IkBa. Among them, Choi et al (2018) have also observed the alleviation of phosphorylated IKK complex.…”

“…TUS, the main component of T. farfara, was described to have anti-platelet-aggregation and cardiovascular-respiratory stimulating effects in previous studies (Hwang et al, 1987;Li and Wang, 1988). In recent years, several studies have proven beneficial in the treatment of diseases such as diabetic obesity (Park et al, 2008), cancers , and various inflammatory diseases (Lee et al, 2016;Kim et al, 2017b;Cheon et al, 2018;Choi et al, 2018;Hwang et al, 2018).…”

“…In terms of molecular mechanism, many studies have indicated that TUS suppresses exogenous-agent-stimulated inflammation by downregulating NF-kB signaling in different samples including human colonic tissues, airway epithelial cells, and dendritic and microglial cells (Park et al, 2014;Cheon et al, 2018;Choi et al, 2018;Hwang et al, 2018). Some scholars have reported that TUS may repress the MAPK signaling (including JNK, ERK, and p38 pathways) and then decrease production of inflammatory mediators in different cell lines and animal models (Kim et al, 2017b;Hwang et al, 2018). Moreover, TUS was proven to regulate cancer cell proliferation, angiogenesis, and inflammation via Wnt, VEGFR2, and Irf and heme oxygenase-1 (HO-1) pathways, respectively Park et al, 2014; 2019).…”

“…TUS was previously proved to alleviate LPS-stimulated inflammatory reaction in RAW264.7 and cecal ligation and p u n c t u r e (C L P ) -i n d u c e d s e p t i c m u r i n e m o d e l by downregulating NF-kB and MAPK pathways (Kim et al, 2017b). However, osteoclast over-activation by aseptic inflammation is also a main factor of osteoclast-dominated osteolytic diseases like aseptic prosthetic loosening.…”

“…Previous studies have suggested that this natural compound exerts therapeutic effects in inflammatory pulmonary diseases (Choi et al, 2018), inflammatory intestinal diseases (IBD) (Cheon et al, 2018), ischemic stroke (Hwang et al, 2018), colon cancer , obesity and type 2 diabetes (Park et al, 2008), demonstrating diverse effect in regulating pathophysiological changes like anti-inflammation (Hwangbo et al, 2009;Lee et al, 2016;Kim et al, 2017b), antioxidation (Park et al, 2014;Qin et al, 2014), antitumor . Especially, TUS was found to attenuate lipopolysaccharide (LPS)-induced inflammatory mediator production in RAW264.7 cells via NF-kB and (or) MAPK signaling cascades (Hwangbo et al, 2009;Lee et al, 2016;Kim et al, 2017b), therefore it may be a possible drug candidate for bone protection by suppressing osteoclast formation and activation. However, except for the above-mentioned effects towards osteoclast progenitors and other cell lines, little is known about whether and how TUS suppresses RANKLinduced osteoclast differentiation and improves periprosthetic osteolysis-induced aseptic prosthetic loosening in vivo.…”