Abstract
Tetrastigma hemsleyanum Diels et Gilg is a valuable Chinese medicinal herb with a long history of clinical application. Our previous study isolated and characterized a purified polysaccharide from the aerial part of Tetrastigma hemsleyanum (SYQP) and found it having antipyretic and antitumor effects in mice. A preliminary mechanistic study suggests these effects may be related to the binding of toll-like receptor (TLR4). The objective of this study is to further explore the detailed stimulating characteristics of SYQP on TLR4 signaling pathway and its in vivo immune regulating effect. We use HEK-BLUE hTLR4, mouse and human macrophage cell lines, as research tools. In vitro results show SYQP activated HEK-BLUE hTLR4 instead of HEK-BLUE Null cells. The secretion and the mRNA expression of cytokines related to TLR4 signaling significantly increased after SYQP treatment in both PMA-induced THP-1 and RAW264.7 macrophage cell lines. The TLR4 antagonist TAK-242 can almost completely abolish this activation. Furthermore, molecules such as IRAK1, NF-κB, MAPKs, and IRF3 in both the MyD88 and TRIF branches were all activated without pathway selection. In vivo results show SYQP enhanced antigen-specific spleen lymphocyte proliferation and serum IgG levels in OVA-immunized C57BL/6 mice. Orally administered 200 mg/kg SYQP induced obvious tumor regression, spleen weight increase, and the upregulation of the mRNA expression of TLR4-related cytokines in Lewis lung carcinoma–bearing mice. These results indicate SYQP can act as both a human and mouse TLR4 agonist and enhance immune responses in mice (p < 0.05). This study provides a basis for the development and utilization of SYQP as a new type of TLR4 agonist in the future.
Highlights
The toll-like receptor (TLR) family is a class of patternrecognition receptors of mammalian species, which can identify conservative molecules of pathogenic microorganisms and regulate the natural and acquired immune responses of organisms (Akira and Takeda, 2004)
In the purification of the polysaccharides obtained from Tetrastigma hemsleyanum, gradient elution was carried out and a relatively strong peak was observed in the fraction eluted by 0.2 mol/L NaCl solution as shown in Supplemental Figure S1
The main findings of the present study are that SYQP can stimulate both human and mouse TLR4 in macrophage cell lines and show immune adjuvant and anticancer activity in vivo
Summary
The toll-like receptor (TLR) family is a class of patternrecognition receptors of mammalian species, which can identify conservative molecules of pathogenic microorganisms and regulate the natural and acquired immune responses of organisms (Akira and Takeda, 2004). TLR4 was the first member to be found, and it is unique for its ability to induce both MyD88-dependent and -independent (TRIF) pathways. Activation of TLR4 receptor on antigen presenting cells can promote the uptake, processing, and presentation of foreign antigens, which is helpful to activate T cells and enhance the antigen-specific immune response. Recent studies show that TLR4 agonists can break tumor-induced immune tolerance and enhance the innate and adaptive immune responses against cancer (Boushehri Shetab and Lamprecht, 2018). Type I IFNs can further promote the secretion of IP-10 and upregulate the expression of MHCI on tumor cells, enhancing the antitumor CD8+ T cell effector response (Najbauer et al, 2019). TLR4 receptor agonists with the ability to activate both MyD88-dependent and -independent pathways are promising drugs for cancer immunotherapy
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