Rosenstiel Philip, Sina Christian, End Caroline, Renner Marcus, Lyer Stefan, Till Andreas, Hellmig Stephan, Nikolaus Susanna, Fölsch Ulrich R, Helmke Burkhard, Autschbach Frank, Schirmacher Peter, Kioschis Petra, Hafner Mathias, Poustka Annemarie, Mollenhauer Jan, Schreiber Stefan
Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstrache 12, Kiel, Germany.
J Immunol. 2007 Jun 15;178(12):8203-11. doi: 10.4049/jimmunol.178.12.8203.
Mucosal epithelial cell layers are constantly exposed to a complex resident microflora. Deleted in malignant brain tumors 1 (DMBT1) belongs to the group of secreted scavenger receptor cysteine-rich proteins and is considered to be involved in host defense by pathogen binding. This report describes the regulation and function of DMBT1 in intestinal epithelial cells, which form the primary immunological barrier for invading pathogens. We report that intestinal epithelial cells up-regulate DMBT1 upon proinflammatory stimuli (e.g., TNF-alpha, LPS). We demonstrate that DMBT1 is a target gene for the intracellular pathogen receptor NOD2 via NF-kappaB activation. DMBT1 is strongly up-regulated in the inflamed intestinal mucosa of Crohn's disease patients with wild-type, but not with mutant NOD2. We show that DMBT1 inhibits cytoinvasion of Salmonella enterica and LPS- and muramyl dipeptide-induced NF-kappaB activation and cytokine secretion in vitro. Thus, DMBT1 may play an important role in the first line of mucosal defense conferring immune exclusion of bacterial cell wall components. Dysregulated intestinal DMBT1 expression due to mutations in the NOD2/CARD15 gene may be part of the complex pathophysiology of barrier dysfunction in Crohn's disease.
黏膜上皮细胞层不断暴露于复杂的常驻微生物群中。恶性脑肿瘤缺失基因1（DMBT1）属于富含半胱氨酸的分泌型清道夫受体蛋白家族，被认为通过与病原体结合参与宿主防御。本报告描述了DMBT1在肠道上皮细胞中的调节及功能，肠道上皮细胞构成了抵御入侵病原体的主要免疫屏障。我们发现，促炎刺激（如肿瘤坏死因子-α、脂多糖）可使肠道上皮细胞上调DMBT1。我们证明，DMBT1是细胞内病原体受体NOD2通过激活核因子κB的靶基因。在野生型而非突变型NOD2的克罗恩病患者炎症性肠黏膜中，DMBT1强烈上调。我们表明，DMBT1在体外可抑制肠炎沙门氏菌的细胞侵袭以及脂多糖和胞壁酰二肽诱导的核因子κB激活和细胞因子分泌。因此，DMBT1可能在黏膜防御的第一线发挥重要作用，赋予对细菌细胞壁成分的免疫排斥。由于NOD2/CARD15基因突变导致的肠道DMBT1表达失调可能是克罗恩病屏障功能障碍复杂病理生理学的一部分。
