Chemoattraction of macrophages, T lymphocytes, and mast cells is evolutionarily conserved within the human α-defensn family
Chemoattraction of macrophages, T lymphocytes, and mast cells is evolutionarily conserved within the human α-defensn family
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DOI：
10.4049/jimmunol.179.6.3958
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发表时间：
2007-09-15
影响因子：
4.4
通讯作者：
Zwirner, Joerg
中科院分区：
文献类型：
--
作者：
Grigat, Jasmin;Soruri, Afsaneh;Zwirner, Joerg
人类防御素是天然的多肽抗生素。根据六个保守的半胱氨酸残基的位置和结合，它们被分为两个家族，分别命名为α-和β-防御素。人类α-防御素主要在中性粒细胞(人中性粒细胞多肽(HNP)1-4)或肠道潘氏细胞(人防御素(HD)5和6)表达。虽然α-防御素与炎症性肠病的发病机制有关，但其免疫调节功能尚不清楚。在本研究中，发现HNP-1、HNP-3和HD5对巨噬细胞有很强的趋化作用，但对树突状细胞则不是，使用Gα(I)蛋白和MAPK作为信号转导。α-防御素对人肥大细胞系HMC-1也有趋化作用，但与β-防御素相比，它缺乏诱导细胞内钙离子流动的能力。此外，HNP-1、HNP-3和HD5对幼稚T淋巴细胞和记忆性T淋巴细胞的动员作用相当。使用蛋白激酶C抑制剂GF109和666976，我们观察到人α-防御素之间发生了不依赖蛋白激酶C的功能脱敏，这表明免疫细胞上存在一个共同的HNP-1、HNP-3和HD5受体。这种α-防御素受体可以被PKC激活剂PMA异源脱敏，也可以被人β-防御素依赖的PKC交叉脱敏。相反，α-防御素以PKC依赖的方式使β-防御素介导的免疫细胞迁移变得不敏感，这表明这两个防御素家族都有独特的受体。综上所述，我们的观察表明，巨噬细胞、T淋巴细胞和肥大细胞的趋化作用代表了一种免疫调节功能，这种功能在进化上在人类α-防御素家族中是保守的，并受到β-防御素的严格调控。
Human defensins are natural peptide antibiotics. On the basis of the position and bonding of six conserved cysteine residues, they are divided into two families, designated alpha- and beta-defensins. Human alpha-defensins are expressed predominantly in neutrophils (human neutrophil peptides (HNP) 1-4) or intestinal Paneth cells (human defensins (HD) 5 and 6). Although a-defensins have been implicated in the pathogenesis of inflammatory bowel disease, their immunomodulatory functions are poorly understood. In the present study, HNP-1, HNP-3, and HD5 were found to be potent chemotaxins for macrophages but not dendritic cells using G alpha(i) proteins and MAPK as signal transducers. alpha-Defensins were also chemoattractive for the human mast cell line HMC-1 but lacked, in contrast to beta-defensins, the ability to induce intracellular calcium fluxes. Furthermore, HNP-1, HNP-3, and HD5 comparably mobilized naive as well as memory T lymphocytes. Using the protein kinase C (PKC) inhibitors GF109 and 666976, we observed a PKC-independent functional desensitization to occur between human a-defensins, which suggests a common receptor for HNP-1, HNP-3, and HD5 on immune cells. This a-defensin receptor was subject to heterologous desensitization by the PKC activator PMA and to PKC-dependent cross-desensitization by human beta-defensins. Conversely, a-defensins desensitized beta-defensin-mediated migration of immune cells in a PKC-dependent manner, suggesting unique receptors for both defensin families. Taken together, our observations indicate that chemoattraction of macrophages, T lymphocytes, and mast cells represents an immunomodulatory function which is evolutionarily conserved within the human alpha-defensin family and tightly regulated by beta-defensins.