Yang Yi, Inatsuka Carol, Gad Ekram, Disis Mary L, Standish Leanna J, Pugh Nirmal, Pasco David S, Lu Hailing
Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, WA, USA.
Bastyr University, Kenmore, WA, USA.
Innate Immun. 2014 Nov;20(8):857-66. doi: 10.1177/1753425913513814. Epub 2013 Dec 9.
Inflammasome activation has been shown to regulate both innate and adaptive immune responses. It is important to investigate whether immune-enhancing natural products can also activate inflammasome. The current study examined the potential of protein-bound polysaccharide-K (PSK), a hot water extract from Trametes versicolor, to activate inflammasome. Using THP-1 cells, we have demonstrated that PSK induces both pro-IL-1β and mature IL-1β in THP-1 cells in a caspase 1- and NLRP3-dependent manner. PSK also induces IL-1β and IL-18 in human PBMC. Cathepsin B is required for PSK-induced inflammasome activation as CA-074-Me, a cathepsin B inhibitor, significantly decreased PSK-induced IL-1β. PSK induces NLRP3 at both mRNA and protein level. Comparison of PSK-induced IL-1β in bone marrow-derived macrophages from wild type C57BL/6 mice, TLR2(-/-), P2X7R(-/-) and NLRP3(-/-) mice demonstrated that PSK-induced IL-1β is dependent on both TLR2 and NLRP3. P2X7R is not required for PSK-induced inflammasome activation, but enhances PSK-induced caspase-1 activation and IL-1β induction. Altogether, these results demonstrated that PSK induces inflammasome activation and production of IL-1β in a TLR2- and NLRP3-dependent mechanism. These results provide novel insights into the mechanisms of the immune modulatory effects of PSK.
炎症小体激活已被证明可调节先天性和适应性免疫反应。研究免疫增强型天然产物是否也能激活炎症小体很重要。当前研究检测了云芝热水提取物蛋白结合多糖K（PSK）激活炎症小体的潜力。利用THP-1细胞，我们证明PSK以半胱天冬酶1和NLRP3依赖的方式在THP-1细胞中诱导前白细胞介素-1β和成熟白细胞介素-1β。PSK还能在人外周血单核细胞中诱导白细胞介素-1β和白细胞介素-18。组织蛋白酶B是PSK诱导炎症小体激活所必需的，因为组织蛋白酶B抑制剂CA-074-Me能显著降低PSK诱导的白细胞介素-1β。PSK在mRNA和蛋白质水平上均诱导NLRP3。比较野生型C57BL/6小鼠、TLR2（-/-）、P2X7R（-/-）和NLRP3（-/-）小鼠骨髓来源巨噬细胞中PSK诱导的白细胞介素-1β，结果表明PSK诱导的白细胞介素-1β依赖于TLR2和NLRP3。P2X7R不是PSK诱导炎症小体激活所必需的，但能增强PSK诱导的半胱天冬酶-1激活和白细胞介素-1β诱导。总之，这些结果表明PSK以TLR2和NLRP3依赖的机制诱导炎症小体激活和白细胞介素-1β的产生。这些结果为PSK免疫调节作用的机制提供了新的见解。
