Medicinal Plant Research 2025, Vol.15, No.3, 129-141 http://hortherbpublisher.com/index.php/mpr 133 4 Immunomodulatory Effects of Ginsenosides 4.1 Regulation of innate immunity Ginsenosides exert their functions by regulating the activation state of innate immune cells, especially macrophages, and the secretion of cytokines. Whether it is PPD or PPT-type ginsenosides, they can promote or inhibit the activity of macrophages, according to different environments and concentrations (You et al., 2022; Paik et al., 2023; Qian et al., 2024; Zhang et al., 2024). For instance, Rg1 and Rg3 can promote the polarization of macrophages to the anti-inflammatory M2 type, reduce the production of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, and increase the levels of anti-inflammatory factors IL-10 (Paik et al., 2023; Qian et al., 2024). Ginsenosides can also inhibit the activation of inflammasomes (NLRP3), further reducing the inflammatory response (Zhao et al., 2024). Under the action of ginsenosides, the phagocytic activity of macrophages and the production of reactive oxygen species (ROS) are enhanced, which is conducive to pathogen clearance (Yang et al., 2018). Ginsenosides, especially Rg1, have also been shown to promote the maturation of dendritic cells (DCs), manifested as increased expression of surface markers, like CD86, and enhanced secretion of IL-12 and TNF-α (Qu et al., 2011). Mature DCs can enhance antigen presentation and T cell activation ability (Tang et al., 2024; Zhang et al., 2024). In vivo experiments, Rg1 can increase the number of DCs, and enhance their ability to stimulate T and B lymphocytes, thereby playing a role between innate immunity and adaptive immunity (Tang et al., 2024). 4.2 Influence on adaptive immunity Ginsenosides affect the immune response of T helper cells (Th), by regulating the differentiation of T cell subsets. For instance, Rg1 can promote Th2 differentiation, enhance IL-4 production, and simultaneously inhibit Th1 response (IFN-γ), thereby improving the pathological state characterized by Th1 dominance (You et al., 2022). Other ginsenosides, like Rd and Rg3, can simultaneously enhance the production of Th1 and Th2 cytokines and maintain the balance of the immune response (Guo et al., 2022). Under the action of ginsenosides, the humoral immune function is also enhanced. Studies have shown that, Rg1, Rg2 and Re can promote B cell proliferation and antibody production, increase the levels of IgG, IgA and IgM in animal models, and act as adjuvants to enhance the antibody response induced by vaccines (You et al., 2022; Guo et al., 2022; Tang et al., 2024). This effect is partially achieved by activating T follicular helper cells (Tfh), and promoting cytokines that support B cell differentiation and function (Dong et al., 2017; Guo et al., 2022). 4.3 Cross-regulation of inflammation and immunity Ginsenosides exhibit dual immunomodulatory effects, and can act as either immunostimulants or immunosuppressants depending on the immune environment (You et al., 2022; Zhang et al., 2024). For instance, Rg1 and CK can enhance immune tolerance, while suppressing excessive inflammatory responses. The mechanisms include promoting Treg differentiation, and inhibiting Th17-mediated inflammation (Dong et al., 2017). Ginsenosides finely regulate immune responses by regulating a wide range of signaling pathways, including NF-κB, MAPK, PI3K/Akt and STAT (Cheng et al., 2019; Tang et al., 2024; Zhang et al., 2024). They can down-regulate pro-inflammatory cytokines (TNF-α, IL-1β, IL-6 etc.), and up-regulate anti-inflammatory mediators (such as IL-10), thereby contributing to the resolution of inflammation and the restoration of immune homeostasis (You et al., 2022; Paik et al., 2023; Zhang et al., 2024). 5 Cellular and Molecular Evidence of Anti-inflammatory Mechanisms 5.1 Cell-based studies A large number of studies using LPS-stimulated macrophage models, especially RAW264.7 cells and bone marrow-derived macrophages, have clarified the anti-inflammatory effects of ginsenosides. Studies have shown that ginsenosides, such as Rb1, Rg1, Rg3, Rh2, Rh4, compound K and Rc, can inhibit pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in these models. And the production of inflammatory mediators (iNOS, COX-2, NO, PGE2)
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