Xinchuan Zheng

Garcinia mangostana L. (mangosteen) is a tropical fruit that has been used for medicinal purposes in Southeast Asia for centuries. With an interest in its applications to treat infection, we sought to investigate the bioactive constituents of mangosteen and identified the phenolic compound procyanidin B2 from the mangosteen pericarp by examining lipopolysaccharide (LPS) binding capacity. The LPS binding and neutralization activities of procyanidin B2 were determined by a combination of biophysical and in silico techniques. The affinity of procyanidin B2 to LPS was 1.61 × 10^–5 M. Procyanidin B2 significantly neutralized LPS and selectively inhibited the LPS-induced release of tumor necrosis factor (TNF)-α from RAW264.7 cells in a dose-dependent manner. Binding thermodynamics revealed favorable hydrogen bonding and hydrophobic interactions between procyanidin B2 and LPS. Molecular simulations suggested that hydrogen bonding and hydrophobic interactions were involved in the binding process. These findings have, for the first time, shed light on the anti-inflammatory properties of procyanidin B2 through LPS binding and neutralization and provided a promising lead for the development of antiendotoxin agents.

A growing body of literature suggests that most chronic autoimmune diseases are associated with inappropriate inflammation mediated by Toll-like receptor (TLR) 3, TLR7/8, or TLR9. Therefore, research into blocking TLR activation to treat these disorders has become a hot topic. Here, we report the immunomodulatory properties of a nonstimulatory CpG-containing oligodeoxynucleotide (CpG-ODN), CpG-c41, which had previously only been known as a TLR9 antagonist. In this study, we found that both in vitro and in vivo CpG-c41 decreased levels of various proinflammatory factors that were induced by single activation or coactivation of intracellular TLRs, but not membrane-bound TLRs, no matter what downstream signal pathways the TLRs depend on. Moreover, CpG-c41 attenuated excessive inflammation in the imiquimod-induced psoriasis-like mouse model of skin inflammation by suppressing immune cell infiltration and release of inflammatory factors. We also found evidence that the immunosuppressive effects of CpG-c41 on other intracellular TLRs are mediated by a TLR9-independent mechanism. These results suggest that CpG-c41 acts as an upstream of signaling cascades, perhaps on the processes of ligand internalization and transfer. Taken together, these results suggest that CpG-c41 disrupts various aspects of intracellular TLR activation and provides a deeper insight into the regulation of innate immunity.