Abstract
BackgroundBrazilian green propolis is produced by mixing secretions from Africanized honey bees with exudate, mainly from Baccharis dracunculifolia. Brazilian propolis is especially rich in flavonoids and cinammic acid derivatives, and it has been widely used in folk medicine owing to its anti-inflammatory, anti-viral, tumoricidal, and analgesic effects. Moreover, it is applied to prevent metabolic disorders, such as type 2 diabetes and arteriosclerosis. Previously, we demonstrated that propolis ethanol extract ameliorated type 2 diabetes in a mouse model through the resolution of adipose tissue inflammation. The aims of this study were to identify the immunosuppressive cells directly elicited by propolis extract and to evaluate the flavonoids that induce such cells.MethodsEthanol extract of Brazilian propolis (PEE; 100 mg/kg i.p., twice a week) was injected into lean or high fat-fed obese C57BL/6 mice or C57BL/6 ob/ob mice for one month. Subsequently, immune cells in visceral adipose tissue and the peritoneal cavity were monitored using FACS analysis. Isolated macrophages and the macrophage-like cell line J774.1 were treated with PEE and its constituent components, and the expression of immune suppressive myeloid markers were evaluated. Finally, we injected one of the identified compounds, kaempferol, into C57BL/6 mice and performed FACS analysis on the adipose tissue.ResultsIntraperitoneal treatment of PEE induces CD11b+, Gr-1+ myeloid-derived suppressor cells (MDSCs) in visceral adipose tissue and the peritoneal cavity of lean and obese mice. PEE directly stimulates cultured M1 macrophages to transdifferentiate into MDSCs. Among twelve compounds isolated from PEE, kaempferol has an exclusive effect on MDSCs induction in vitro. Accordingly, intraperitoneal injection of kaempferol causes accumulation of MDSCs in the visceral adipose tissue of mice.ConclusionBrazilian PEE and its compound kaempferol strongly induce MDSCs in visceral adipose tissue at a relatively early phase of inflammation. Given the strong anti-inflammatory action of MDSCs, the induction of MDSCs by PEE and kaempferol is expected to be useful for anti-diabetic and anti-inflammatory therapies.Graphical
Highlights
Brazilian green propolis is produced by mixing secretions from Africanized honey bees with exudate, mainly from Baccharis dracunculifolia
Propolis ethanol extract increases number of CD11b+, Gr-1+ Myeloid-derived suppressor cell (MDSC) in the visceral adipose tissue of obese and lean mice Changes in the numbers of eosinophils and M1 macrophages were observed in a previous study four months after beginning injections of propolis ethanol extract (PEE) (100 mg/kg i.p.) twice weekly [27]
fluorescence-activated cell sorting (FACS) analysis indicated that PEE increased the number of eosinophils by about 2-fold in the mesenteric adipose tissue (Fig. 1a)
Summary
Brazilian green propolis is produced by mixing secretions from Africanized honey bees with exudate, mainly from Baccharis dracunculifolia. We demonstrated that propolis ethanol extract ameliorated type 2 diabetes in a mouse model through the resolution of adipose tissue inflammation. The imbalance of adipose tissue macrophages is triggered by cytokines released by enlarged adipocytes, as well as an accumulation of immune cells [4]. Type 2 innate lymphoid cells and their target eosinophils repress M1 macrophage activation in adipose tissue, and subsequently attenuate metabolic disorders [5, 6]. Regulatory T cells inhibit chronic inflammation by the secretion of anti-inflammatory cytokines, such as interleukin (IL)-10 and transforming growth factor (TGF)-β1 [7, 8]. Myeloid derived-suppressor cells (MDSCs) are another cell type that has the potential to modulate inflammation [9,10,11]. Manipulation of MDSCs is beneficial in anti-diabetic treatment, an induction procedure for MDSCs has not yet been established
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