Japonicone A antagonizes the activity of TNF-α by directly targeting this cytokine and selectively disrupting its interaction with TNF receptor-1

Abstract

Anti-TNF biologics are effective therapies for various inflammatory diseases. Unfortunately, their clinical use is associated with an increased risk of infections. Selectively inhibiting TNF receptor-1 (TNFR1)-mediated signaling while preserving TNFR2 signaling may reduce inflammation yet maintain host immune response to pathogens. However, few small molecules that selectively target the TNF/TNFR system have been discovered. In the present study, we identified Japonicone A (Jap A), a nature compound derived from Inula japonica Thunb, as a novel TNF-α antagonist, as it reduced the TNF-α-mediated cytotoxicity on L929 cells and inhibited the binding of (125)I-labeled TNF-α to L929 cell surface. Furthermore, Jap A could directly bind to TNF-α rather than TNFR1 as determined by surface plasmon resonance. More importantly, Jap A could effectively inhibit the binding of TNF-α to TNFR1, while displaying only marginal inhibitory effects on that to TNFR2. Jap A also could block TNFR1-mediated signaling as it inhibited TNF-α-induced NF-κB activation in 293 cells. In addition, Jap A suppressed TNF-α-induced expressions of adhesion molecules (ICAM-1, VCAM-1) and chemokine (MCP-1) in the endothelial cells by blocking TNF-α-triggered multiple signaling pathways. Data from in vivo experiments demonstrated that Jap A protected mice from acute hepatitis induced by TNF-α/d-galactosamine, but did not compromise host antiviral immunity in adenovirus-infected mice. These results indicate that Jap A can directly target TNF-α, selectively disrupt its interaction with TNFR1, and antagonize its pro-inflammatory activities without compromising host defense against virus, thus emphasizing the potential of Jap A as an interesting lead compound for development of new anti-inflammatory drugs.