Okroj Marcin, Hsu Yi-Fan, Ajona Daniel, Pio Ruben, Blom Anna M
Lund University, Department of Laboratory Medicine, Section of Clinical Chemistry, University Hospital, S-205 02 Malmö, Sweden.
Mol Immunol. 2008 Jan;45(1):169-79. doi: 10.1016/j.molimm.2007.04.025. Epub 2007 Jun 4.
The complement system is important for protection from invading pathogens, removal of waste products and guidance of the immune response. Furthermore, complement can be also targeted to cancer cells. However, membrane-bound inhibitors over-expressed by certain types of tumor cells restrict the cytotoxic activity of complement. Herein we report that non-small cell lung cancer (NSCLC) cells produce soluble complement inhibitors factor I (FI) and C4b-binding protein (C4BP). FI is a serine protease capable of degrading the activated complement components C3b and C4b, whilst C4BP acts as its cofactor. Furthermore, NSCLC cells express membrane-bound regulators and shed membrane cofactor protein (MCP), which shares cofactor function with C4BP. Secretion of FI from NSCLC cells was higher than previously reported for any non-hepatic source and FI produced by these cells could efficiently support cleavage of C3b and C4b. In vitro functional assays revealed that additional FI significantly decreased C3 deposition and complement-dependent lysis, particularly when cofactors were added. Our results demonstrate that soluble inhibitors produced by NSCLC cells may provide further protection from complement beyond the level ensured by membrane-bound inhibitors and, as such, contribute to the aggressive phenotype of these lung cancer cells.
补体系统对于抵御入侵病原体、清除废物产物以及引导免疫反应至关重要。此外，补体也可作用于癌细胞。然而，某些类型肿瘤细胞过度表达的膜结合抑制剂会限制补体的细胞毒性活性。在此我们报告，非小细胞肺癌（NSCLC）细胞会产生可溶性补体抑制剂I因子（FI）和C4b结合蛋白（C4BP）。FI是一种丝氨酸蛋白酶，能够降解活化的补体成分C3b和C4b，而C4BP作为其辅因子发挥作用。此外，NSCLC细胞表达膜结合调节因子并释放膜辅因子蛋白（MCP），MCP与C4BP具有共同的辅因子功能。NSCLC细胞分泌的FI高于此前报道的任何非肝脏来源，且这些细胞产生的FI能够有效促进C3b和C4b的裂解。体外功能试验表明，额外的FI显著降低了C3沉积和补体依赖性细胞溶解，尤其是在添加辅因子时。我们的结果表明，NSCLC细胞产生的可溶性抑制剂可能为癌细胞提供超出膜结合抑制剂所提供水平的对补体的进一步保护，因此有助于这些肺癌细胞的侵袭性表型。
