Specific-sized Hyaluronan Fragments Promote Expression of Human β-Defensin 2 in Intestinal Epithelium
Specific-sized Hyaluronan Fragments Promote Expression of Human β-Defensin 2 in Intestinal Epithelium
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DOI：
10.1074/jbc.m112.356238
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发表时间：
2012-08-31
影响因子：
4.8
通讯作者：
de la Motte, Carol A.
中科院分区：
文献类型：
--
作者：
Hill, David R.;Kessler, Sean P.;de la Motte, Carol A.
透明质酸（HA）是一种糖胺聚糖聚合物，存在于几乎所有哺乳动物组织的细胞外基质中。最近的工作表明，小的片段化HA聚合物通过与先天分子模式识别受体（如TLR 4）相互作用在免疫细胞、内皮和表皮中引发先天防御反应中的作用。尽管有这些进展，但关于片段化HA在肠上皮中的作用知之甚少，其中许多模式识别受体充当先天防御反应的哨兵，其在存在丰富和多样的微生物挑战的情况下维持上皮屏障完整性。在这里，我们报告说，HA片段促进表达的先天抗菌肽人类β-防御素2（H β D2）在肠上皮细胞。用HA片段制剂处理HT-29结肠上皮细胞导致H β D2蛋白以片段大小特异性方式表达呈时间和剂量依赖性上调，其中35 kDa HA片段制剂成为细胞内H β D2最有效的诱导剂。此外，特定大小的HA片段的口服给药促进了野生型和CD 44缺陷小鼠的结肠上皮中H β D2直系同源物的表达，但在TLR 4缺陷小鼠中没有。总之，我们的观察结果表明，一个高度尺寸特异性，TLR 4依赖性，先天防御反应片段HA有助于肠上皮屏障防御通过诱导细胞内H β D2蛋白。
Hyaluronan (HA) is a glycosaminoglycan polymer found in the extracellular matrix of virtually all mammalian tissues. Recent work has suggested a role for small, fragmented HA polymers in initiating innate defense responses in immune cells, endothelium, and epidermis through interaction with innate molecular pattern recognition receptors, such as TLR4. Despite these advances, little is known regarding the effect of fragmented HA at the intestinal epithelium, where numerous pattern recognition receptors act as sentinels of an innate defense response that maintains epithelial barrier integrity in the presence of abundant and diverse microbial challenges. Here we report that HA fragments promote expression of the innate antimicrobial peptide human beta-defensin 2 (H beta D2) in intestinal epithelial cells. Treatment of HT-29 colonic epithelial cells with HA fragment preparations resulted in time- and dose-dependent up-regulated expression of H beta D2 protein in a fragment size-specific manner, with 35-kDa HA fragment preparations emerging as the most potent inducers of intracellular H beta D2. Furthermore, oral administration of specific-sized HA fragments promotes the expression of an H beta D2 ortholog in the colonic epithelium of both wild-type and CD44-deficient mice but not in TLR4-deficient mice. Together, our observations suggest that a highly size-specific, TLR4-dependent, innate defense response to fragmented HA contributes to intestinal epithelium barrier defense through the induction of intracellular H beta D2 protein.