Division of Dermatology and Venereology, Lund University, Biomedical Center, Lund, Sweden.
J Innate Immun. 2011;3(5):471-82. doi: 10.1159/000327016. Epub 2011 May 11.
Serine proteases of the S1 family have maintained a common structure over an evolutionary span of more than one billion years, and evolved a variety of substrate specificities and diverse biological roles, involving digestion and degradation, blood clotting, fibrinolysis and epithelial homeostasis. We here show that a wide range of C-terminal peptide sequences of serine proteases, particularly from the coagulation and kallikrein systems, share characteristics common with classical antimicrobial peptides of innate immunity. Under physiological conditions, these peptides exert antimicrobial effects as well as immunomodulatory functions by inhibiting macrophage responses to bacterial lipopolysaccharide. In mice, selected peptides are protective against lipopolysaccharide-induced shock. Moreover, these S1-derived host defense peptides exhibit helical structures upon binding to lipopolysaccharide and also permeabilize liposomes. The results uncover new and fundamental aspects on host defense functions of serine proteases present particularly in blood and epithelia, and provide tools for the identification of host defense molecules of therapeutic interest.
丝氨酸蛋白酶 S1 家族在超过十亿年的进化过程中保持着共同的结构，并进化出了多种底物特异性和多样化的生物学功能，涉及消化和降解、血液凝固、纤维蛋白溶解和上皮稳态。我们在这里表明，广泛的丝氨酸蛋白酶的 C 端肽序列，特别是来自凝血和激肽系统的序列，与先天免疫的经典抗菌肽具有共同的特征。在生理条件下，这些肽通过抑制巨噬细胞对细菌脂多糖的反应，发挥抗菌作用和免疫调节功能。在小鼠中，选定的肽对脂多糖诱导的休克具有保护作用。此外，这些源自 S1 的宿主防御肽与脂多糖结合时呈现螺旋结构，并且还能使脂质体穿孔。这些结果揭示了丝氨酸蛋白酶在血液和上皮中特有的宿主防御功能的新的和基本的方面，并为鉴定具有治疗意义的宿主防御分子提供了工具。
