Reduced expression of Paneth cell antimicrobial -defensins, human defensin (HD)-5 and

Reduced expression of Paneth cell antimicrobial -defensins, human defensin (HD)-5 and -6, characterizes Crohn’s disease (CD) of the ileum. only and 784 CD patients with ileal involvement were used to determine frequency distributions. We found an association of rs3814570 with ileal CD but neither with colonic CD or UC, in a combined analysis (allele positivity: OR 1.27, 95% CI 1.07 to 1 1.52, p?=?0.00737), which was the strongest in ileal CD patients with stricturing behaviour (allele frequency: OR 1.32, 95% CI 1.08 to1.62, p?=?0.00686) or an additional involvement of the upper GIT (allele frequency: OR 1.38, 95% CI 1.03 to1.84, p?=?0.02882). The newly identified genetic association of with ileal CD provides evidence that the decrease in Paneth cell -defensins is a primary factor in disease pathogenesis. Introduction Inflammatory bowel 1194044-20-6 supplier disease (IBD), a chronic inflammation of the intestine, is commonly classified into ulcerative colitis (UC) and Crohn’s disease (CD) on the basis of clinical features and histopathology [1]. Whereas UC is typically restricted to the colon, CD can occur at many sites, predominantly in the small intestinal ileum, the colon, or in both locations. Emerging details of disease pathogenesis support the current concept that ongoing immune activation in IBD is driven SMARCB1 by bacterial microbiota, possibly as a result to an attenuated antimicrobial barrier in genetically predisposed individuals [1]C[3]. Both UC and CD have a complex polygenic, multifactorial background, with a coincidence of susceptibility genes and environmental factors involved in pathogenesis. It is likely that different genetically affected factors may explain the various clinical patterns of IBD, especially location of disease in CD, which is stable over time [4]C[6]. Different explanations for disease location, including a central role of small intestinal Paneth cells and other defects in intestinal innate immunity, were the focus of recent discussion [2]. For ileal CD, reduced expression of small intestinal Paneth cell -defensins HD-5 and -6 (DEFA5 and DEFA6) has been described in several cohorts [7]C[12]. The defensin deficiency is proposed to attenuate the antibacterial host defense capacity of the intestinal mucosa, and may initiate and/or perpetuate the chronic inflammation characterizing the disease at this site [7]C[12]. We recently reported one mechanism to explain, in part, the decrease of these antimicrobial peptides [9], [13]: A reduced expression of the Wnt pathway transcription factor TCF-4 (also known as transcription factor 7-like 2), which directly controls Paneth cell defensin expression (HD-5, HD-6, and orthologous mouse cryptdin peptides [9], [13]). Wnt proteins are a family of secreted morphogenes that 1194044-20-6 supplier play an important role in regulating cell fate and differentiation during embryogenesis [14]. The Wnt signalling pathway is induced by binding of Wnt family proteins to cell surface receptors, leading to stabilization of cytoplasmatic -catenin, translocation of this regulatory protein into the nucleus, formation of a complex with transcription factors of the Tcf/Lef family and subsequently the activation of various target genes [13]. In the small intestine, epithelial cells transit through differentiation steps initiated in progenitor cells, which reside adjacent to Paneth cells at the base of the crypts [15]. Wnt 1194044-20-6 supplier signalling helps to maintain an undifferentiated state of the intestinal stem cells [16], [17] and, paradoxically, also regulates positioning, differentiation and maturation of Paneth cells [13], [18]. The Paneth cell gene program is critically dependent on TCF-4 [13]. Using a rodent model, we observed that very small changes (a 50% decrease of TCF-4 levels) are sufficient to compromise mouse Paneth cell cryptidin expression as well as its corresponding antimicrobial function against several bacterial species. We also reported that a reduced level of TCF-4 expression and activity was associated with a decrease of Paneth cell -defensin levels in CD of the small intestine. The decrease of TCF-4 expression was found to be independent of inflammation in the tissue specimens, and also independent of the 1007fsinsC SNP in mRNA levels in these studies, an aberration in the promoter region of could be a possible explanation. Thus, the aim of this study was to sequence the promoter region of the gene in a group of patients with ileal CD to identify potential polymorphisms and to perform a subsequent association study on candidate genetic variants in well-defined cohorts of patients. We identified a total of 8 SNP variants, of which three (rs3814570, rs10885394, rs10885395) were in linkage.