Productive role of fractalkine and CXCL16 in human epidermal keratinocytes

CXCL16是一种CXC趋化因子受体CXCR6的配体。CXCL16是以膜结合形式合成的，被切割成可溶性形式，对表达CXCR6的细胞，如活化的CD8T细胞、NKT细胞以及Th1极化的CD4和CD8T细胞具有趋化作用。相比之下，表达在人巨噬细胞和树突状细胞上的一种膜结合形式的CXCL16作为氧化型低密度脂蛋白的清道夫受体。此外，表达在巨噬细胞上的CXCL16还介导了大肠杆菌或金黄色葡萄球菌等细菌的黏附和吞噬。CXCL16的可溶性趋化素结构域在浓度为5-g/ml时对金黄色葡萄球菌和大肠杆菌具有抗菌活性。加入10-g/ml的可溶性CXCL16可使金黄色葡萄球菌和大肠杆菌的存活率分别降低70%和40%。由于CXCL16是由HEK组成性地产生的，因此CXCL16在人体皮肤中参与了与微生物病原体相关的宿主防御功能以及防御。趋化因子Fractalkine/CX3CL1是以膜结合的形式合成的，并被蛋白酶转化为可溶性形式(S)。由于Fractalkine招募CX3CR1阳性细胞，如NK细胞和CD8+T细胞，它被认为参与了炎症反应中将这些细胞招募到表皮中。为了解决这个问题，我们调查了正常人角质形成细胞是否能在细胞因子存在的情况下产生分裂因子。肿瘤坏死因子、白介素1和干扰素协同促进干扰素诱导的正常人角质形成细胞产生Fractalkine。总之，这是第一个表明正常人角质形成细胞产生可溶性Fractalkine蛋白的报告。

CXCL16 is a ligand for CXCR6, a CXC-chemokine receptor. CXCL16 is synthesized as a membrane-bound form that is cleaved to a soluble form that is a chemoattractant for CXCR6-expressing cells such as activated CD8 T cells, NKT cells, and Th1-polarized CD4 and CD8 T cells. By contrast, a membrane-bound form of CXCL16 expressed on human macrophages and dendritic cells acts as a scavenger receptor for oxidized low density lipoprotein. In addition, CXCL16 expressed on macrophages mediates adhesion and phagocytosis of bacteria such as Escheria coli or Staphylococcus aureus. The soluble chemokine domain of CXCL16 at concentrations > 5 □g/ml had antimicrobial activity against S.aureus and E.coli. Addition of 10 □g/ml soluble CXCL16 reduced the survival rate of S.aureus and E.coli by 70 and 40%, respectively. Because CXCL16 is produced constitutively by HEK, CXCL16 contributes to host-defense function in relation to microbial pathogens in human skin as well as □-defensins.Fractalkine/CX3CL1, a chemokine, is synthesized as a membrane bound form and converted to a soluble form by protease(s). Since fractalkine recruits CX3CR1 positive cells such as NK cells and CD8+ T cells, it is supposed to be involved in recruiting these cells into the epidermis in the inflammatory reaction. To address this issue, we investigated whether normal human keratinocytes can produce fractalkine in the presence of cytokines. TNF-□, IL1-□□ and IFN-□ synergistically enhanced IFN-□-induced fractalkine production in normal human keratinocytes. In conclusion, this is the first report showing that normal human keratinocytes produce soluble fractalkine protein.