Bacterial exotoxins downregulate cathelicidin (hCAP-18/LL-37) and human β-defensin 1 (HBD-1) expression in the intestinal epithelial cells
Bacterial exotoxins downregulate cathelicidin (hCAP-18/LL-37) and human β-defensin 1 (HBD-1) expression in the intestinal epithelial cells
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DOI：
10.1111/j.1462-5822.2008.01227.x
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发表时间：
2008-12-01
影响因子：
3.4
通讯作者：
Das, Santasabuj
中科院分区：
文献类型：
--
作者：
Chakraborty, Krishnendu;Ghosh, Shubhamoy;Das, Santasabuj
Cathelicidin（hCAP-18/LL-37）和β-防御素1（HBD-1）是具有高基础表达水平的人抗微生物肽（AMP），其形成宿主抵抗上皮表面感染的第一道防线。抗微生物功能归因于它们的直接杀微生物作用以及免疫调节作用。病原微生物已经开发出多种模式，包括转录抑制以对抗宿主免疫应答的这一分支。确切的机制和病原体衍生的分子负责转录下调仍然未知。在这里，我们已经表明，肠道病原体抑制LL-37和HBD-1在肠上皮细胞（IEC）的表达与霍乱弧菌和肠致病性大肠杆菌（ETEC）发挥最显着的效果。霍乱毒素（CT）和不稳定毒素（LT）分别是霍乱弧菌和ETEC的主要毒力蛋白，在体外和体内都是造成这些效应的主要原因。CT通过激活几种细胞内信号通路下调AMP，包括蛋白激酶A（PKA）、ERK MAP激酶和cAMP积累下游的考克斯-2，诱导型cAMP早期阻遏物（ICER）可能至少部分介导CT的这种作用。这是第一个报告，以显示转录抑制的AMP通过激活细胞信号转导途径的已知的致病微生物的毒力蛋白。
Cathelicidin (hCAP-18/LL-37) and beta-defensin 1 (HBD-1) are human antimicrobial peptides (AMPs) with high basal expression levels, which form the first line of host defence against infections over the epithelial surfaces. The antimicrobial functions owe to their direct microbicidal effects as well as the immunomodulatory role. Pathogenic microorganisms have developed multiple modalities including transcriptional repression to combat this arm of the host immune response. The precise mechanisms and the pathogen-derived molecules responsible for transcriptional downregulation remain unknown. Here, we have shown that enteric pathogens suppress LL-37 and HBD-1 expression in the intestinal epithelial cells (IECs) with Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC) exerting the most dramatic effects. Cholera toxin (CT) and labile toxin (LT), the major virulence proteins of V. cholerae and ETEC, respectively, are predominantly responsible for these effects, both in vitro and in vivo. CT transcriptionally downregulates the AMPs by activating several intracellular signalling pathways involving protein kinase A (PKA), ERK MAPKinase and Cox-2 downstream of cAMP accumulation and inducible cAMP early repressor (ICER) may mediate this role of CT, at least in part. This is the first report to show transcriptional repression of the AMPs through the activation of cellular signal transduction pathways by well-known virulence proteins of pathogenic microorganisms.