Queensland Institute of Medical Research, Australian Center for International and Tropical Health, Griffith Medical Research College, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
J Immunol. 2010 Mar 1;184(5):2663-70. doi: 10.4049/jimmunol.0902187. Epub 2010 Feb 3.
SerpinB2 (plasminogen activator inhibitor-2) is widely described as an inhibitor of urokinase plasminogen activator; however, SerpinB2(-/-) mice show no detectable increase in urokinase plasminogen activator activity. In this study, we describe an unexpected immune phenotype in SerpinB2(-/-) mice. After immunization with OVA in CFA, SerpinB2(-/-) mice made approximately 6-fold more IgG2c and generated approximately 2.5-fold more OVA-specific IFN-gamma-secreting T cells than SerpinB2(+/+) littermate controls. In SerpinB2(+/+) mice, high inducible SerpinB2 expression was seen at the injection site and in macrophages low levels in draining lymph nodes and conventional dendritic cells, and no expression was seen in plasmacytoid dendritic, B, T, or NK cells. SerpinB2(-/-) macrophages promoted greater IFN-gamma secretion from wild-type T cells in vivo and in vitro and, when stimulated with anti-CD40/IFN-gamma or cultured with wild-type T cells in vitro, secreted more Th1-promoting cytokines than macrophages from littermate controls. Draining lymph node SerpinB2(-/-) myeloid APCs similarly secreted more Th1-promoting cytokines when cocultured with wild-type T cells. Regulation of Th1 responses thus appears to be a physiological function of inflammation-associated SerpinB2; an observation that may shed light on human inflammatory diseases like pre-eclampsia, lupus, asthma, scleroderma, and periodontitis, which are associated with SerpinB2 polymorphisms or dysregulated SerpinB2 expression.
丝氨酸蛋白酶抑制剂 B2（纤溶酶原激活物抑制剂-2）广泛被描述为尿激酶纤溶酶原激活物的抑制剂；然而，丝氨酸蛋白酶抑制剂 B2（-/-）小鼠中尿激酶纤溶酶原激活物的活性并没有明显增加。在这项研究中，我们描述了丝氨酸蛋白酶抑制剂 B2（-/-）小鼠一个出乎意料的免疫表型。在用 CFA 中的 OVA 免疫后，丝氨酸蛋白酶抑制剂 B2（-/-）小鼠产生的 IgG2c 约增加 6 倍，OVA 特异性 IFN-γ 分泌 T 细胞约增加 2.5 倍，而丝氨酸蛋白酶抑制剂 B2（+/+）同窝对照小鼠则没有。在丝氨酸蛋白酶抑制剂 B2（+/+）小鼠中，在注射部位和引流淋巴结中的巨噬细胞中可以观察到高诱导性的丝氨酸蛋白酶抑制剂 B2 表达，而在常规树突状细胞、浆细胞样树突状细胞、B 细胞、T 细胞或 NK 细胞中则没有表达。丝氨酸蛋白酶抑制剂 B2（-/-）巨噬细胞在体内和体外促进野生型 T 细胞产生更多的 IFN-γ，并在受到抗 CD40/IFN-γ刺激或与体外野生型 T 细胞共培养时，分泌的促 Th1 细胞因子比同窝对照的巨噬细胞更多。引流淋巴结中的丝氨酸蛋白酶抑制剂 B2（-/-）髓样 APC 与野生型 T 细胞共培养时，同样分泌更多的促 Th1 细胞因子。因此，Th1 反应的调节似乎是炎症相关丝氨酸蛋白酶抑制剂 B2 的一种生理功能；这一观察结果可能为子痫前期、狼疮、哮喘、硬皮病和牙周炎等与丝氨酸蛋白酶抑制剂 B2 多态性或失调的丝氨酸蛋白酶抑制剂 B2 表达相关的人类炎症性疾病提供启示。
