Blaber Sachiko I, Ciric Bogoljub, Christophi George P, Bernett Matthew J, Blaber Michael, Rodriguez Moses, Scarisbrick Isobel A
Institute of Molecular Biophysics, Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, USA.
FASEB J. 2004 May;18(7):920-2. doi: 10.1096/fj.03-1212fje. Epub 2004 Mar 19.
Kallikrein 6 (K6, MSP) is a newly identified member of the Kallikrein family of serine proteases that is preferentially expressed in the adult central nervous system (CNS). We have previously demonstrated that K6 is abundantly expressed by inflammatory cells at sites of CNS inflammation and demyelination in animal models of multiple sclerosis (MS) and in human MS lesions. To test the hypothesis that this novel enzyme is a mediator of pathogenesis in CNS inflammatory disease, we have evaluated whether autonomously generated K6 antibodies alter the clinicopathological course of disease in murine proteolipid protein139-151-induced experimental autoimmune encephalomyelitis (PLP139-151 EAE). We demonstrate that immunization of mice with recombinant K6 generates antibodies that block K6 enzymatic activity in vitro, including the breakdown of myelin basic protein (MBP), and that K6-immunized mice exhibit significantly delayed onset and severity of clinical deficits. Reduced clinical deficits were reflected in significantly less spinal cord pathology and meningeal inflammation and in reduced Th1 cellular responses in vivo and in vitro. These data demonstrate for the first time that K6 participates in enzymatic cascades mediating CNS inflammatory disease and that this unique enzyme may represent a novel therapeutic target for the treatment of progressive inflammatory disorders, including MS.
激肽释放酶6（K6，MSP）是丝氨酸蛋白酶激肽释放酶家族新发现的成员，在成体中枢神经系统（CNS）中优先表达。我们之前已证明，在多发性硬化症（MS）动物模型及人类MS病灶的CNS炎症和脱髓鞘部位，炎性细胞大量表达K6。为验证这种新型酶是CNS炎性疾病发病机制介质的假说，我们评估了自主产生的K6抗体是否会改变小鼠脂蛋白139 - 151诱导的实验性自身免疫性脑脊髓炎（PLP139 - 151 EAE）的临床病理过程。我们证明，用重组K6免疫小鼠可产生在体外阻断K6酶活性的抗体，包括髓鞘碱性蛋白（MBP）的降解，且K6免疫小鼠的临床缺陷发作和严重程度显著延迟。临床缺陷减轻表现为脊髓病理和脑膜炎症显著减轻，以及体内外Th1细胞反应减弱。这些数据首次证明K6参与介导CNS炎性疾病的酶促级联反应，且这种独特的酶可能代表治疗包括MS在内的进行性炎性疾病的新型治疗靶点。
