IL-1β-specific up-regulation of neutrophil gelatinase-associated lipocalin is controlled by IκB-ξ
IL-1β-specific up-regulation of neutrophil gelatinase-associated lipocalin is controlled by IκB-ξ
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DOI：
10.4049/jimmunol.176.9.5559
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发表时间：
2006-05-01
影响因子：
4.4
通讯作者：
Borregaard, Niels
中科院分区：
文献类型：
--
作者：
Cowland, Jack B.;Muta, Tatsushi;Borregaard, Niels
中性粒细胞明胶酶相关脂质运载蛋白（NGAL）是一种铁载体结合蛋白，通过螯合铁发挥抑菌作用。已在肺和结肠的发炎上皮中观察到NGAL合成的强诱导。在肺上皮细胞系A549中，NGAL的表达被IL-1 β上调，但不被TNF-α上调，尽管这两种细胞因子诱导NF-κ B结合NGAL启动子。在这项研究中，我们提出的证据表明，IL-1 β的特异性是由NGAL启动子的NF-κ B结合辅因子I κ B-ζ的转录激活的要求。IL-1 β刺激后A549细胞中NGAL表达的上调依赖于从头蛋白质合成，并且通过对I κ B-zeta mRNA的小干扰而大大减少。用表达IKB-zeta的质粒共转染A549细胞使TNF-α能够诱导NGAL转录，表明IKB-zeta诱导是区分IL-1 β和TNF-α诱导NGAL表达能力的唯一因素。与IKB-zeta密切相关的辅因子Bcl-3的共表达不能使TNF-α诱导NGAL转录。NGAL启动子的功能性NF-κ B位点是IKB-zeta发挥其作用所必需的。人β防御素2基因在A549细胞中的IL-1 β特异性诱导也需要IKB-zeta。我们的研究结果表明，一个共同的监管机制已经发展到控制表达的抗菌蛋白在上皮细胞中表达的一个子集。
Neutrophil gelatinase-associated lipocalin (NGAL) is a siderophore-binding protein that exerts a bacteriostatic effect by sequestering iron. Strong induction of NGAL synthesis has been observed in inflamed epithelium of the lungs and colon. Expression of NGAL is up-regulated in the lung epithelial cell line A549 by IL-1 beta, but not by TNF-alpha, despite an induction of NF-kappa B binding to the NGAL promoter by both cytokines. In this study, we present evidence that the IL-1 beta specificity is caused by a requirement of the NGAL promoter for the NF-kappa B-binding cofactor I kappa B-zeta for transcriptional activation. Up-regulation of NGAL expression in A549 cells following IL-1 beta stimulation was dependent on de novo protein synthesis and was greatly diminished by a small interfering against I kappa B-zeta mRNA. Cotransfection of A549 cells with a plasmid expressing I kappa B-zeta made TNF-alpha capable of inducing NGAL transcription, indicating that IKB-zeta induction is the only factor discriminating between IL-1 beta and TNF-alpha in their ability to induce NGAL expression. Coexpression of the cofactor Bcl-3, which is closely related to IKB-zeta, did not enable TNF-alpha to induce NGAL transcription. A functional NF-kappa B site of the NGAL promoter was required for IKB-zeta to exert its effect. The human beta defensin 2 gene also required IKB-zeta for its IL-1 beta-specific induction in A549 cells. Our findings indicate that a common regulatory mechanism has evolved to control expression of a subset of antimicrobial proteins expressed in epithelial cells.