Tanaka S, Murakami T, Horikawa H, Sugiura M, Kawashima K, Sugita T
Lead Generation Research Laboratory, Tanabe Seiyaku Co., LTD., Osaka, Japan.
Int J Immunopharmacol. 1997 Jan;19(1):15-24. doi: 10.1016/s0192-0561(97)00004-0.
Dipeptidyl peptidase IV (DP IV, CD26) is a serine exoprotease which selectively cleaves the penultimate proline residue of polypeptides. This enzyme is also expressed as a surface marker on activated T cells. In order to assess the relevance of DP IV in immunological disorders, we evaluated the in vivo effects of specific DP IV inhibitors using two arthritis models, one which was induced by collagen one by alkyldiamine. These animal models share several pathological features associated with rheumatoid arthritis. The transition state substrate analog of DP IV, (S)-Alanylpyrrolidine-boronic Acid (Ala-boroPro), suppressed hind paw swelling, which was associated with collagen-induced and alkyldiamine-induced arthritis. A competitive inhibitor of DP IV, Lys(Z(NO2))-thiazolidide and an irreversible inhibitor, Ala-Pro-nitrobenzoylhydroxylamine also suppressed alkyldiamine-induced arthritis dose-dependently. We also analyzed the pharmacological effects of Lys(Z(NO2))-thiazolidide on several immune responses in vitro, in order to determine its mode of action. This inhibitor suppressed mitogen-induced and antigen-induced proliferation of T cells. However, studies using splenic cells from DP IV deficient rats showed that the inhibition of lymphocyte proliferation was not exerted through the inhibition of DP IV.
二肽基肽酶IV（DP IV，CD26）是一种丝氨酸外切蛋白酶，可选择性切割多肽的倒数第二个脯氨酸残基。这种酶也作为活化T细胞上的表面标志物表达。为了评估DP IV在免疫紊乱中的相关性，我们使用两种关节炎模型评估了特异性DP IV抑制剂的体内作用，一种是由胶原蛋白诱导的，另一种是由烷基二胺诱导的。这些动物模型具有与类风湿性关节炎相关的几种病理特征。DP IV的过渡态底物类似物（S）-丙氨酰吡咯烷-硼酸（Ala-boroPro）抑制后爪肿胀，这与胶原蛋白诱导的和烷基二胺诱导的关节炎有关。DP IV的竞争性抑制剂Lys（Z（NO2））-噻唑烷和不可逆抑制剂Ala-Pro-硝基苯甲酰羟胺也剂量依赖性地抑制烷基二胺诱导的关节炎。我们还分析了Lys（Z（NO2））-噻唑烷在体外对几种免疫反应的药理作用，以确定其作用方式。这种抑制剂抑制有丝分裂原诱导的和抗原诱导的T细胞增殖。然而，使用DP IV缺陷大鼠的脾细胞进行的研究表明，淋巴细胞增殖的抑制不是通过抑制DP IV来实现的。
