Mortier Anneleen, Gouwy Mieke, Van Damme Jo, Proost Paul, Struyf Sofie
KU Leuven University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Immunology, Leuven, Belgium.
KU Leuven University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Immunology, Leuven, Belgium
J Leukoc Biol. 2016 Jun;99(6):955-69. doi: 10.1189/jlb.3MR0915-401R. Epub 2016 Jan 7.
Post-translational modification of chemokines is an essential regulatory mechanism to enhance or dampen the inflammatory response. CD26/dipeptidylpeptidase IV, ubiquitously expressed in tissues and blood, removes NH2-terminal dipeptides from proteins with a penultimate Pro or Ala. A large number of human chemokines, including CXCL2, CXCL6, CXCL9, CXCL10, CXCL11, CXCL12, CCL3L1, CCL4, CCL5, CCL11, CCL14, and CCL22, are cleaved by CD26; however, the efficiency is clearly influenced by the amino acids surrounding the cleavage site and although not yet proven, potentially affected by the chemokine concentration and interactions with third molecules. NH2-terminal cleavage of chemokines by CD26 has prominent effects on their receptor binding, signaling, and hence, in vitro and in vivo biologic activities. However, rather than having a similar result, the outcome of NH2-terminal truncation is highly diverse. Either no difference in activity or drastic alterations in receptor recognition/specificity and hence, chemotactic activity are observed. Analogously, chemokine-dependent inhibition of HIV infection is enhanced (for CCL3L1 and CCL5) or decreased (for CXCL12) by CD26 cleavage. The occurrence of CD26-processed chemokine isoforms in plasma underscores the importance of the in vitro-observed CD26 cleavages. Through modulation of chemokine activity, CD26 regulates leukocyte/tumor cell migration and progenitor cell release from the bone marrow, as shown by use of mice treated with CD26 inhibitors or CD26 knockout mice. As chemokine processing by CD26 has a significant impact on physiologic and pathologic processes, application of CD26 inhibitors to affect chemokine function is currently explored, e.g., as add-on therapy in viral infection and cancer.
趋化因子的翻译后修饰是增强或减弱炎症反应的重要调节机制。CD26/二肽基肽酶IV在组织和血液中广泛表达，可从倒数第二个氨基酸为脯氨酸（Pro）或丙氨酸（Ala）的蛋白质中去除氨基末端二肽。包括CXCL2、CXCL6、CXCL9、CXCL10、CXCL11、CXCL12、CCL3L1、CCL4、CCL5、CCL11、CCL14和CCL22在内的大量人类趋化因子可被CD26切割；然而，切割效率明显受切割位点周围氨基酸的影响，尽管尚未得到证实，但可能受趋化因子浓度以及与第三分子相互作用的影响。CD26对趋化因子的氨基末端切割对其受体结合、信号传导以及体外和体内生物学活性均有显著影响。然而，氨基末端截短的结果并非相似，而是高度多样。要么活性无差异，要么受体识别/特异性以及趋化活性发生剧烈改变。类似地，CD26切割可增强（对于CCL3L1和CCL5）或降低（对于CXCL12）趋化因子依赖性的HIV感染抑制作用。血浆中出现经CD26处理的趋化因子异构体突出了体外观察到的CD26切割的重要性。通过调节趋化因子活性，CD26可调节白细胞/肿瘤细胞迁移以及祖细胞从骨髓中的释放，这在使用CD26抑制剂处理的小鼠或CD26基因敲除小鼠中得到了证实。由于CD26对趋化因子的加工对生理和病理过程有重大影响，目前正在探索应用CD26抑制剂来影响趋化因子功能，例如作为病毒感染和癌症的辅助治疗。
