Abstract
BackgroundPolysaccharopeptide (PSP), isolated from Coriolus versicolor COV-1 strain, is a protein-bound polysaccharide widely used as immunoadjuvant for cancer immunotherapy. Although the immunomodulatory activity of PSP has been well established, the precise molecule mechanisms of its biological activity have yet to be fully elucidated.MethodsIn the present study, we first investigated the immunomodulatory activity of PSP in peritoneal macrophages from C57BL/10J (TLR4+/+) and C57BL/10ScCr (TLR4-/-) mice carrying a defective toll-like receptor-4 (TLR4) gene and then evaluated PSP for its effect on tumor inhibition rates and the immune organ index in above two different strains of mice. In addition, PSP were also evaluated for its activation of TLR4, TLR4-downstream molecules (TRAF6, NF-κB and AP-1) in spleens of tumor-bearing C57BL/10J (TLR4+/+) and C57BL/10ScCr (TLR4-/-) mice.ResultsThe results showed that PSP had adjuvant activities in stimulating expressions of cytokines as well as TLR4, TRAF6, phosphorylation of NF-κB p65 transcription factors and phosphorylation of c-Jun (a component of the transcription factor AP-1) in peritoneal macrophages from C57BL/10J (TLR4+/+) mice but not from C57BL/10ScCr (TLR4-/-) mice. In vivo PSP as well as Adriamycin (ADM) decreased the mean weights of tumors compared with normal saline and PSP increased thymus index and spleen index relative to ADM in tumor-bearing C57BL/10J (TLR4+/+) mice but not in C57BL/10ScCr (TLR4-/-) mice.ConclusionsWe demonstrated that PSP activates peritoneal macrophages in vitro via TLR4 signaling pathway and PSP functions its immunoregulatory effect in vivo also via TLR4 signaling pathway. These data strongly suggest TLR4 signaling pathway is involved in PSP-mediated immunomodulatory activities.
Highlights
Polysaccharopeptide (PSP), isolated from Coriolus versicolor COV-1 strain, is a protein-bound polysaccharide widely used as immunoadjuvant for cancer immunotherapy
In order to verify if Toll-like receptors 4 (TLR4) was required for PSP activation of macrophages, peritoneal macrophages from ScCr (TLR4−/−) and B10 (TLR4+/+) mice were incubated with PSP (25 μg/ml) or LPS (100 ng/ml) as a positive control for 24 h and assayed for TNF-α and IL-6 concentration in their culture supernatant
LPS and PSP failed to induce IL-6 secretion in ScCr mice (Fig. 1b). These results suggest that TLR4 is involved in PSP activation of murine macrophages
Summary
Polysaccharopeptide (PSP), isolated from Coriolus versicolor COV-1 strain, is a protein-bound polysaccharide widely used as immunoadjuvant for cancer immunotherapy. Recent researches indicated that the immunoregulatory effects of polysaccharides are related to the Toll-like receptors (TLR) signaling pathway [15, 16], and Toll-like receptors 4 (TLR4) plays a central role in the enhancement of the innate immune response and the production of cytokine induced by polysaccharides [17,18,19,20]. A family of TLRs plays an important role in the recognition of molecular structures that are shared by many pathogens in the host defense system [21, 22]. Our previous studies have reported that PSP has an immunoregulatory effect through the TLR4 signaling pathway in human peripheral blood mononuclear cells (PBMCs) [28]
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