Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-22184 Lund, Sweden.
J Immunol. 2013 Jun 15;190(12):6303-10. doi: 10.4049/jimmunol.1203030. Epub 2013 May 8.
The abundant serine proteinase inhibitor heparin cofactor II (HCII) has been proposed to inhibit extravascular thrombin. However, the exact physiological role of this plasma protein remains enigmatic. In this study, we demonstrate a previously unknown role for HCII in host defense. Proteolytic cleavage of the molecule induced a conformational change, thereby inducing endotoxin-binding and antimicrobial properties. Analyses employing representative peptide epitopes mapped these effects to helices A and D. Mice deficient in HCII showed increased susceptibility to invasive infection by Pseudomonas aeruginosa, along with a significantly increased cytokine response. Correspondingly, decreased levels of HCII were observed in wild-type animals challenged with bacteria or endotoxin. In humans, proteolytically cleaved HCII forms were detected during wounding and in association with bacteria. Thus, the protease-induced uncovering of cryptic epitopes in HCII, which transforms the molecule into a host defense factor, represents a previously unknown regulatory mechanism in HCII biology and innate immunity.
肝素辅因子 II（HCII）是一种丰富的丝氨酸蛋白酶抑制剂，被认为能够抑制血管外的凝血酶。然而，这种血浆蛋白的确切生理作用仍然是个谜。在这项研究中，我们证明了 HCII 在宿主防御中的一个先前未知的作用。该分子的蛋白水解切割诱导构象变化，从而诱导内毒素结合和抗菌特性。利用代表性肽表位的分析将这些效应映射到 A 螺旋和 D 螺旋上。缺乏 HCII 的小鼠对铜绿假单胞菌的侵袭性感染易感性增加，同时细胞因子反应明显增加。相应地，在受到细菌或内毒素挑战的野生型动物中观察到 HCII 水平降低。在人类中，在创伤期间和与细菌相关时检测到蛋白水解切割的 HCII 形式。因此，蛋白酶诱导 HCII 中隐藏表位的暴露，将该分子转化为宿主防御因子，代表了 HCII 生物学和先天免疫中以前未知的调节机制。
