Expression and function of Toll-like receptors 2 and 4 in human keratinocytes
Expression and function of Toll-like receptors 2 and 4 in human keratinocytes
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DOI：
10.1093/intimm/dxg068
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发表时间：
2003-06-01
影响因子：
4.4
通讯作者：
Kemény, L
中科院分区：
文献类型：
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作者：
Pivarcsi, A;Bodai, L;Kemény, L
角质形成细胞有能力通过产生抗菌物质来杀死病原体和细菌。最近的研究表明，微生物成分利用人类Toll样受体(TLR)家族的信号分子在各种细胞中传递信号。在这里，我们提供了角质形成细胞在mRNA和蛋白水平表达TLR2和TLR4的证据，并表明TLR2和TLR4存在于活体人类表皮中，并且它们的表达受到微生物成分的调节。角质形成细胞也表达髓系分化蛋白基因(MyD88)，该基因参与了许多TLR的信号转导途径。脂多糖+干扰素-γ使TLR2和TLR4的表达分别增加50倍和5倍。白念珠菌、甘露聚糖、结核分枝杆菌或干扰素-γ联合作用于角质形成细胞后，可引起核转录因子-kappaB的活化和核转位。抑制核因子-kappaB可阻断角质形成细胞对念珠菌的杀伤活性，提示角质形成细胞的抗菌作用需要激活核因子-kappaB。内毒素+干扰素-γ、白色念珠菌(4个/kC)、肽聚糖(1个/ml)或结核分枝杆菌提取物可显著增加IL-8基因的表达(P<；0.05)。比0-h水平分别增加了15倍、8倍、10.8倍和7倍。抗TLR2和抗TLR4中和抗体可抑制微生物化合物诱导的IL-8基因表达增加，提示TLRs参与了病原体诱导的促炎细胞因子的表达。我们的发现强调了角质形成细胞作为天然免疫组成部分的重要性。
Keratinocytes have the ability to kill pathogenic fungi and bacteria by producing antimicrobial substances. Recent studies suggest that microbial components use signaling molecules of the human Toll-like receptor (TLR) family to transduce signals in various cells. Here we provide evidence that keratinocytes express both TLR2 and TLR4 at the mRNA and protein levels, and show that TLR2 and TLR4 are present in the normal human epidermis in vivo and that their expression is regulated by microbial components. The expression of myeloid differentiation protein gene (MyD88), which is involved in the signaling pathway of many TLR, was also demonstrated in keratinocytes. LPS + IFN-gamma increased the expression of TLR2 and TLR4 50- and 5-fold respectively. Treatment of keratinocytes with Candida albicans, mannan, Mycobacterium tuberculosis or LIPS with IFN-gamma resulted in the activation and nuclear translocation of NF-kappaB Inhibition of NF-kappaB blocked the Candida-killing activity of keratinocytes, suggesting that the antimicrobial effect of keratinocytes requires NF-kappaB activation. LPS + IFN-gamma, C. albicans (4 Candida/KC), peptidoglycan (1 mug/ml) or M. tuberculosis extract significantly increased IL-8 gene expression after 3 h of treatment (P < 0.05). The increases over the 0-h level were 15-, 8-, 10.8- and 7-fold, respectively. The microbial compound-induced increase in IL-8 gene expression could be inhibited by anti-TLR2 and anti-TLR4 neutralizing antibodies, suggesting that TLRs are involved in the pathogen-induced expression of this pro-inflammatory cytokine. Our findings stress the importance of the role of keratinocytes as a component of innate immunity.