Xanthones from Mangosteen Inhibit Inflammation in Human Macrophages and in Human Adipocytes Exposed to Macrophage-Conditioned Media ,

Abstract

Obesity-associated inflammation is characterized by recruitment of macrophages (MΦ) into white adipose tissue (WAT) and production of inflammatory cytokines, leading to the development of insulin resistance. The xanthones, α- and γ-mangostin (MG), are major bioactive compounds found in mangosteen that are reported to have antiinflammatory and antioxidant properties. Thus, we examined the efficacy of MG to prevent lipopolysaccharide (LPS)-mediated inflammation in human MΦ (differentiated U937 cells) and cross-talk with primary cultures of newly differentiated human adipocytes. We found that α- and γ-MG attenuated LPS-induced expression of inflammatory genes, including tumor necrosis factor-α, interleukin-6, and interferon γ-inducible protein-10 in a dose-dependent manner in MΦ. We also found that α- and γ-MG attenuated LPS-activated mitogen-activated protein kinases (MAPK) and activator protein (AP)-1, but only γ-MG reduced nuclear factor-κB (NF-κB). In addition, α- and γ-MG attenuated LPS suppression of PPARγ gene expression in a dose-dependent manner. Notably, the ability of MΦ-conditioned media to cause inflammation and insulin resistance in primary cultures of human adipocytes was attenuated by pretreating MΦ with γ-MG. Taken together, these data demonstrate that MG attenuates LPS-mediated inflammation in MΦ and insulin resistance in adipocytes, possibly by preventing the activation of MAPK, NF-κB, and AP-1, which are central to inflammatory cytokine production in WAT.