Isoalantolactone suppresses LPS-induced inflammation by inhibiting TRAF6 ubiquitination and alleviates acute lung injury

Abstract

Isoalantolactone (IAL) is a sesquiterpene lactone extracted from roots of Inula helenium L and has shown anti-inflammatory effects. In this study we investigated the therapeutic effects of IAL on acute lung injury (ALI) and elucidated the mechanisms underlying its anti-inflammation potential in vitro and in vivo. Treatment with lipopolysaccharide (LPS, 100 ng/mL) drastically stimulated production of inflammatory mediators such as NO, TNF-α, IL-1β, and IL-6 in mouse bone marrow-derived macrophages (BMDMs), which was dose-dependently suppressed by pretreatment with IAL (2.5, 5, 10, 20 μM). We further revealed that IAL suppressed LPS-induced NF-κB, ERK, and Akt activation. Moreover, the downregulation of non-degradable K63-linked polyubiquitination of TRAF6, an upstream transcription factor of NF-κB, contributed to the anti-inflammatory effects of IAL. ALI was induced in mice by intratracheal injection of LPS (5 mg/kg). Administration of IAL (20 mg/kg, i.p.) significantly suppressed pulmonary pathological changes, neutrophil infiltration, pulmonary permeability, and pro-inflammatory cytokine expression. Our results demonstrate that IAL is a potential therapeutic reagent against inflammation and ALI.

Protective Effect of Piceatannol Against Acute Lung Injury Through Protecting the Integrity of Air-Blood Barrier and Modulating the TLR4/NF-κB Signaling Pathway Activation

“…walls, is generally recognized as the key factor to induce ALI. Challenge with LPS can result in inflammatory cell infiltration, generate a large number of pro-inflammatory cytokines, and then cause the lung tissues damage (Huang et al, 2018;Ding et al, 2019). In the present study, we found that treatment of PIC significantly reversed the increases of cell infiltration and the levels of pro-inflammatory cytokines including TNF-a and IL-1b both in lung and BALF induced by LPS.…”

Dehydrocostus Lactone Suppresses LPS-induced Acute Lung Injury and Macrophage Activation through NF-κB Signaling Pathway Mediated by p38 MAPK and Akt

“…Through the years, many of SLs have been reported to be effective on treatment of inflammation. For example, isoalantolactone, a sesquiterpene lactone extracted from roots of Inula helenium L, was identified to suppress LPS-induced lung injury and proinflammatory cytokine expression [10]; budlein A can reduce the proinflammatory cytokines and neutrophil recruitment in a model of acute gout arthritis [34]. DHL is a sesquiterpene lactone which has been extensively reported to exhibit anti-tumor and hepatoprotective activities [20,21,35], while the effect of DHL on ALI is rarely examined.…”

“…Lipopolysaccharide (LPS), a main component of bacterial cell walls, has been identified as a key factor in ALI/ ARDS development. Exposure to LPS causes inflammatory cell infiltration, leading to generation of cytokines and chemokines that subsequently lead to initiation and propagation of the inflammation response seen in ALI/ARDS [10]. LPS binds Toll-like receptor 4 (TLR4) on the cell surface which then stimulates the recruitment and activation of the adaptor protein myeloid differentiation primary response gene 88 (MYD88) to the receptor complex, in turn leading to the activation of intracellular pathways [11,12].…”

Isoalantolactone Enhances the Antimicrobial Activity of Penicillin G against Staphylococcus aureus by Inactivating β-Lactamase during Protein Translation

“…Taken together, the data from our research showed that IAL is potentially useful for the treatment of S. aureus pneumonia when used in combination with β-lactam antibiotics. In addition, IAL was administered by subcutaneous administration at a dose of 30 mg/kg, which had no macroscopic toxic effects, and no obvious adverse reactions were observed in C57/BL6 mice after intraperitoneal injection with IAL (20 mg/kg) [19,21].…”

“…Isoalantolactone (IAL), a eudesmanolide-type sesquiterpene flavonoid compound, has been isolated from Atalantia buxifolia, Artemisia, Carpesium cernuum and Inula helenium, and has been shown to have anti-inflammatory, anticancer, antiparasitic and antivirulence activities [17][18][19][20]. In addition, pharmacological research found that this natural compound is a promising candidate for the treatment of carcinoma in humans [21]. However, the effect of IAL on resistance-related enzymes has not yet been reported.…”