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Abstract：
Cholera toxin B (CTB) is a subunit of cholera toxin, a bacterial enterotoxin secreted by Vibrio cholerae and also functions as an immune adjuvant. However, it remains unclear how CTB activates immune cells. We here evaluated whether or how CTB induces production of a pro-inflammatory cytokine, interleukin-1β (IL-1β). CTB induced IL-1β production not only from bone marrow-derived macrophages (BMMs) but also from resident peritoneal macrophages in synergy with O111:B4-derived lipopolysaccharide (LPS O111:B4) that can bind to CTB. Meanwhile, when prestimulated with O55:B5-derived LPS (LPS O55:B5) that fails to bind to CTB, resident peritoneal macrophages, but not BMMs, produced IL-1β in response to CTB. The CTB-induced IL-1β production in synergy with LPS in both peritoneal macrophages and BMMs was dependent on ganglioside GM1, which is required for internalization of CTB. Notably, not only the NLRP3 inflammasome but also the pyrin inflammasome were involved in CTB-induced IL-1β production from resident peritoneal macrophages, while only the NLRP3 inflammasome was involved in that from BMMs. In response to CTB, a Rho family small GTPase, RhoA, which activates pyrin inflammasome upon various kinds of biochemical modification, increased its phosphorylation at serine-188 in a GM1-dependent manner. This phosphorylation as well as CTB-induced IL-1β productions were dependent on protein kinase A (PKA), indicating critical involvement of PKA-dependent RhoA phosphorylation in CTB-induced IL-1β production. Taken together, these results suggest that CTB, incorporated through GM1, can activate resident peritoneal macrophages to produce IL-1β in synergy with LPS through novel mechanisms in which pyrin as well as NLRP3 inflammasomes are involved.
摘要：
霍乱毒素B(CTB)是霍乱毒素的一个亚单位,一种由霍乱弧菌分泌的细菌肠毒素，也起免疫佐剂的作用。然而,目前尚不清楚CTB如何激活免疫细胞.我们在这里评估CTB是否或如何诱导促炎细胞因子的产生，白细胞介素-1β（IL-1β）。CTB不仅诱导骨髓衍生的巨噬细胞（BMM）产生IL-1β，而且与O111：B4衍生的脂多糖（LPSO111：B4）协同作用，可与CTB结合。同时,当用O55：B5衍生的LPS（LPSO55：B5）预刺激时，不能与CTB结合，常驻腹膜巨噬细胞，但不是BMM，响应CTB产生IL-1β。在腹膜巨噬细胞和BMM中，CTB诱导的IL-1β的产生与LPS协同作用取决于神经节苷脂GM1，这是CTB内化所必需的。值得注意的是,不仅NLRP3炎性体，而且pyrin炎性体也参与CTB诱导的IL-1β从常驻腹膜巨噬细胞产生，而只有NLRP3炎性体参与了来自BMM的炎症。响应CTB，一个Rho家族的小GTPase,RhoA,通过各种生化修饰激活pyrin炎性体，以GM1依赖性方式增加其在丝氨酸-188的磷酸化。这种磷酸化以及CTB诱导的IL-1β产生依赖于蛋白激酶A（PKA），表明PKA依赖性RhoA磷酸化在CTB诱导的IL-1β产生中的关键参与。一起来看,这些结果表明，CTB，通过GM1掺入，可以通过涉及pyrin和NLRP3炎性体的新机制激活常驻腹膜巨噬细胞与LPS协同产生IL-1β。
