Gambogic Acid Disrupts Toll-like Receptor4 Activation by Blocking Lipopolysaccharides Binding to Myeloid Differentiation Factor 2

다국어 초록 (Multilingual Abstract)

Our body’s immune system has defense mechanisms against pathogens such as viruses and bacteria. Immune responses are primarily initiated by the activation of toll-like receptors (TLRs). In particular,TLR4 is well-characterized and is known to be activated by gram-negative bacteria and tissue damage signals. TLR4 requires myeloid differentiation factor 2 (MD2) as a co-receptor to recognize its ligand, lipopolysaccharides(LPS), which is an extracellular membrane component of gram-negative bacteria.
Gambogic acid is a xanthonoid isolated from brownish or orange resin extracted from Garcinia hanburyi. Its primary effect is tumor suppression. Since inflammatory responses are related to the development ofcancer, we hypothesized that gambogic acid may regulate TLR4 activation. Our results demonstrated thatgambogic acid decreased the expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-12, and IL-1β)in both mRNA and protein levels in bone marrow-derived primary macrophages after stimulation withLPS. Gambogic acid did not inhibit the activation of Interferon regulatory factor 3 (IRF3) induced byTBK1 overexpression in a luciferase reporter gene assay using IFN-β-PRD III-I-luc. An in vitro kinaseassay using recombinant TBK1 revealed that gambogic acid did not directly inhibit TBK1 kinase activity,and instead suppressed the binding of LPS to MD2, as determined by an in vitro binding assay and confocalmicroscopy analysis. Together, our results demonstrate that gambogic acid disrupts LPS interactionwith the TLR4/MD2 complex, the novel mechanism by which it suppresses TLR4 activation.

참고문헌 (Reference)

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