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 (ALl) 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 K63-1inked polyubiquitination of TRAF6,an upstream transcription factor of NF-κB,contributed to the anti-inflammatory effects of IAL.ALl 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 ALl.