Abstract
M2-like tumor-associated macrophages (TAMs) in the tumor tissues promote tumor progression by various mechanisms and represent possible targets of antitumor therapy. In the present study, we tested whether compounds from Epimedii Herba inhibit macrophage polarization to the M2/protumorigenic phenotype and prevent tumor progression, using human monocyte-derived macrophages (HMDMs) and an animal sarcoma model. Four Epimedii Herba-derived flavonoid compounds, namely, limonianin, epimedokoreanin B, icaritin, and desmethylicaritin, inhibited CD163 expression and interleukin (IL)-10 production, which are known M2 markers, suggesting that these compounds inhibit M2 polarization. Among these compounds, epimedokoreanin B and limonianin suppressed STAT3 activation in HMDMs. Notably, epimedokoreanin B also suppressed cell proliferation by blocking STAT3 activation in Saos-2 human sarcoma and LM8 mouse sarcoma cell lines. Furthermore, oral administration of epimedokoreanin B inhibited tumor growth in an LM8 tumor-bearing murine model. These results indicate that Epimedii Herba and Epimedii Herba-derived compounds, such as epimedokoreanin B, may be potentially new agents that can be used for the treatment and prevention of various malignant tumors. They may also be promising compounds for targeting the tumor microenvironment by inhibiting M2 polarization of the TAMs.
Highlights
The heterogeneity of macrophage activation plays an important role in innate immunity and is involved in the pathogenesis of various diseases
We first examined the effects of a crude extract prepared from Epimedii Herba on IL-10-induced expression of CD163, an M2 phenotype marker, in human monocyte-derived macrophages (HMDMs) by cell-ELISA
Since the activation of STAT3 contributes to the M2 polarization of macrophages (Mantovani et al, 2002), we examined the effect of limonianin, epimedokoreanin B, icaritin, and desmethylicaritin on IL-10-induced JAK1/STAT3 activation in HMDMs
Summary
The heterogeneity of macrophage activation plays an important role in innate immunity and is involved in the pathogenesis of various diseases. Later, based on arginine metabolism, macrophages were characterized to be of two phenotypes, namely, Th1- and Th2-like phenotypes, described as M1 and M2 phenotypes, respectively (Mills et al, 2000). These concepts have been blended, and the M1/M2 paradigm is well known. M1-like macrophages are proinflammatory, characterized by high levels of IL-1β, tumor necrosis factorα (TNF-α), and IL-23 production, and are involved in the elimination of invading microorganisms. The phenotype of macrophages is highly plastic and can change between the M1 and M2 phenotypes depending on the types of stimulii (Porcheray et al, 2005)
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