Department of Bone Marrow Transplantation, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
Mol Immunol. 2010 Jun;47(10):1890-8. doi: 10.1016/j.molimm.2010.03.014.
Heparanase is an endo-beta-d-glucuronidase that cleaves heparan sulfate (HS) saccharide chains. The enzyme promotes cell adhesion, migration and invasion and plays a significant role in cancer metastasis, angiogenesis and inflammation. The present study focuses on the involvement of heparanase in autoimmunity, applying the murine experimental autoimmune encephalitis (EAE) model, a T-cell dependent disease often used to investigate the pathophysiology of multiple sclerosis (MS). Intraperitoneal administration of recombinant heparanase ameliorated, in a dose dependent manner, the clinical signs of the disease. In vitro and in vivo studies revealed that heparanase inhibited mitogen induced splenocyte proliferation and mixed lymphocyte reaction (MLR) through modulation of their repertoire of cytokines indicated by a marked increase in the levels of IL-4, IL-6 and IL-10, and a parallel decrease in IL-12 and TNF-alpha. Similar results were obtained with active, latent, or point mutated inactive heparanase, indicating that the observed inhibitory effect is attributed to a non-enzymatic activity of the heparanase protein. We suggest that heparanase induces upregulation of Th2 cytokines, resulting in inhibition of the inflammatory lesion of EAE.
乙酰肝素酶是一种内切-β-D-葡糖醛酸酶，能够裂解乙酰肝素硫酸（HS）糖链。该酶促进细胞黏附、迁移和侵袭，并在癌症转移、血管生成和炎症中发挥重要作用。本研究关注乙酰肝素酶在自身免疫中的作用，应用实验性自身免疫性脑脊髓炎（EAE）模型，这是一种依赖于 T 细胞的疾病，常用于研究多发性硬化症（MS）的病理生理学。腹腔内给予重组乙酰肝素酶可剂量依赖性地改善疾病的临床症状。体外和体内研究表明，乙酰肝素酶通过调节细胞因子谱抑制有丝分裂原诱导的脾细胞增殖和混合淋巴细胞反应（MLR），表现为 IL-4、IL-6 和 IL-10 水平显著增加，而 IL-12 和 TNF-α 水平平行降低。活性、潜伏或点突变无活性的乙酰肝素酶也可获得相似的结果，表明观察到的抑制作用归因于乙酰肝素酶蛋白的非酶活性。我们提出，乙酰肝素酶诱导 Th2 细胞因子上调，从而抑制 EAE 的炎症损伤。
