A Sesquiterpene Lactone from a Medicinal Herb Inhibits Proinflammatory Activity of TNF-α by Inhibiting Ubiquitin-Conjugating Enzyme UbcH5

UbcH5 is the key ubiquitin-conjugating enzyme catalyzing ubiquitination during TNF-alpha-triggered NF-kappa B activation. Here, we identified an herb-derived sesquiterpene lactone compound IJ-5 as a preferential inhibitor of UbcH5 and explored its therapeutic value in inflammatory and autoimmune disease models. IJ-5 suppresses TNF-alpha-induced NF-kappa B activation and inflammatory gene transcription by inhibiting the ubiquitination of receptor-interacting protein 1 and NF-kappa B essential modifier, which is essential to I kappa B kinase activation. Mechanistic investigations revealed that IJ-5 preferentially binds to and inactivates UbcH5 by forming a covalent adduct with its active site cysteine and thereby preventing ubiquitin conjugation to UbcH5. In preclinical models, pretreatment of IJ-5 exhibited potent anti-inflammatory activity against TNF-alpha-and D-galactosamine-induced hepatitis and collagen-induced arthritis. These findings highlight the potential of UbcH5 as a therapeutic target for anti-TNF-alpha interventions and provide an interesting lead compound for the development of new anti-inflammation agents.