The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom.
Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.
Front Immunol. 2022 Mar 15;13:832989. doi: 10.3389/fimmu.2022.832989. eCollection 2022.
Several serine proteases have been linked to autoimmune disorders and tumour initiation although the mechanisms are not fully understood. Activation of the kynurenine pathway enzyme indoleamine-2,3-dioxygenase (IDO1) modulates cellular activity in the brain, tolerogenesis in the immune system and is a major checkpoint in cancer development. We now report that mRNA and IDO1 protein expression (generating kynurenine) are induced in human monocyte-derived macrophages by several chymotryptic serine proteases with direct links to tumorigenesis, including Prostate Specific Antigen (PSA), CD26 (Dipeptidyl-peptidase-4, CD26/DPP-4), High Temperature Requirement protein-A (HtrA), and the bacterial virulence factor subtilisin. These proteases also induce expression of the pro-inflammatory cytokine genes and . Other serine proteases tested: bacterial glu-C endopeptidase and mammalian Pro-protein Convertase Subtilase-Kexin-3 (PCSK3, furin), urokinase plasminogen activator (uPA), cathepsin G or neutrophil elastase, did not induce , indicating that the reported effects are not a general property of all serine proteases. The results represent a novel mechanism of activating immunosuppressive and inducing kynurenine generation which, together with the production of inflammatory cytokines, would contribute to tumour initiation and progression, providing a new target for drug development. In addition, the proteasomal S20 serine protease inhibitor carfilzomib, used in the treatment of myeloma, prevented the induction of and cytokine gene expression, potentially contributing to its clinical anti-cancer activity.
几种丝氨酸蛋白酶与自身免疫疾病和肿瘤起始有关，尽管其机制尚未完全阐明。色氨酸途径酶吲哚胺 2,3-双加氧酶（IDO1）的激活调节大脑中的细胞活性、免疫系统中的耐受形成，并且是癌症发展的主要检查点。我们现在报告，几种与肿瘤发生直接相关的糜蛋白酶丝氨酸蛋白酶（包括前列腺特异性抗原（PSA）、CD26（二肽基肽酶-4，CD26/DPP-4）、高热需求蛋白-A（HtrA）和细菌毒力因子枯草溶菌素）诱导人单核细胞衍生巨噬细胞中 mRNA 和 IDO1 蛋白表达（生成犬尿氨酸）。这些蛋白酶还诱导促炎细胞因子基因 和 的表达。测试的其他丝氨酸蛋白酶：细菌 glu-C 内切蛋白酶和哺乳动物 Pro-protein Convertase Subtilase-Kexin-3（PCSK3，furin）、尿激酶纤溶酶原激活物（uPA）、组织蛋白酶 G 或中性粒细胞弹性蛋白酶，没有诱导 ，表明所报道的作用不是所有丝氨酸蛋白酶的一般特性。这些结果代表了一种激活免疫抑制 和诱导犬尿氨酸生成的新机制，与炎症细胞因子的产生一起，将有助于肿瘤起始和进展，为药物开发提供了新的目标。此外，蛋白酶体 S20 丝氨酸蛋白酶抑制剂卡非佐米（carfilzomib），用于治疗骨髓瘤，可防止 和细胞因子基因表达的诱导，可能有助于其临床抗癌活性。
