Kurosaka Kahori, Chen Qian, Yarovinsky Felix, Oppenheim Joost J, Yang De
Laboratory of Molecular Immunoregulation, Center for Cancer Research, and Basic Research Program, Science Applications International Corporation-Frederick, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
J Immunol. 2005 May 15;174(10):6257-65. doi: 10.4049/jimmunol.174.10.6257.
Mammalian antimicrobial proteins, such as defensins and cathelicidin, have stimulating effects on host leukocytes. Cathelin-related antimicrobial peptide (CRAMP), the orthologue of human cathelicidin/LL-37, is the sole identified murine cathelicidin. CRAMP has been shown to have both antimicrobial and angiogenic activities. However, whether CRAMP, like human cathelicidin/LL-37, also exhibits a direct effect on the migration and function of leukocytes is not known. We have observed that CRAMP, like LL-37, was chemotactic for human monocytes, neutrophils, macrophages, and mouse peripheral blood leukocytes. CRAMP also induced calcium mobilization and the activation of MAPK in monocytes. CRAMP-induced calcium flux in monocytes was desensitized by MMK-1, an agonistic ligand specific for formyl peptide receptor-like-1 (FPRL1), and vice versa, suggesting the use of FPRL1 by CRAMP as a receptor. Furthermore, CRAMP induced the chemotaxis of human embryonic kidney 293 cells transfected with either FPRL1 or mouse formyl peptide receptor-2, the mouse homologue of FPRL1, but not by untransfected parental human embryonic kidney 293 cells, confirming the use of FPRL1/mouse formyl peptide receptor-2 by CRAMP. Injection of CRAMP into mouse air pouches resulted in the recruitment predominantly of neutrophils and monocytes, indicating that CRAMP acts as a chemotactic factor in vivo. Finally, simultaneous administration of OVA with CRAMP to mice promoted both humoral and cellular Ag-specific immune responses. Thus, CRAMP functions as both a chemoattractant for phagocytic leukocytes and an enhancer of adaptive immune response.
哺乳动物抗菌蛋白，如防御素和cathelicidin，对宿主白细胞有刺激作用。与人类cathelicidin/LL-37同源的cathelin相关抗菌肽（CRAMP）是唯一已确定的鼠源cathelicidin。CRAMP已被证明具有抗菌和血管生成活性。然而，CRAMP是否像人类cathelicidin/LL-37一样，也对白细胞的迁移和功能有直接影响尚不清楚。我们观察到，CRAMP与LL-37一样，对人类单核细胞、中性粒细胞、巨噬细胞和小鼠外周血白细胞具有趋化作用。CRAMP还诱导单核细胞中的钙动员和丝裂原活化蛋白激酶（MAPK）的激活。CRAMP诱导的单核细胞钙流被MMK-1脱敏，MMK-1是一种对甲酰肽受体样-1（FPRL1）特异的激动剂配体，反之亦然，这表明CRAMP将FPRL1用作受体。此外，CRAMP诱导转染了FPRL1或小鼠甲酰肽受体-2（FPRL1的小鼠同源物）的人类胚胎肾293细胞的趋化作用，但未转染的亲本人类胚胎肾293细胞则无此作用，这证实了CRAMP对FPRL1/小鼠甲酰肽受体-2的利用。将CRAMP注射到小鼠气腔中主要导致中性粒细胞和单核细胞的募集，表明CRAMP在体内作为趋化因子起作用。最后，将OVA与CRAMP同时给予小鼠可促进体液和细胞抗原特异性免疫反应。因此，CRAMP既作为吞噬性白细胞的趋化剂，又作为适应性免疫反应的增强剂发挥作用。
