TSLP is an IL-7-related cytokine mainly expressed by nonhematopoietic cells including epithelial cells and fibroblasts, originally shown to support β-cell development in mice [3, 4]. It was recently shown that TSLP acts on DCs resulting in their activation and induction of a TH2 type immune response [5]. Although sequence homology is weak (43% amino acid sequence identity), human and mice TSLP share similar biological functions [6]. TSLP exerts its activity by binding to a high-affinity heterodimeric receptor that consists of the IL-7 receptor alpha chain (IL-7Rα) and the TSLP receptor (TSLPR) chain and transmits signals via STAT5 activation [7-9]. TSLPR alone

has low affinity for TSLP but together with IL-7Rα forms a high-affinity binding site for TSLP [8, 10]. It has been shown that the interaction TSLP-TSLPR is essential for promoting immune responses against PCI-32765 the intestinal nematode pathogen Trichuris [11,

12]. TSLP is expressed at several mucosal surfaces such as skin, lungs, thymus, and gut, but most of the studies focused on its functions in allergic diseases such as asthma and skin atopic dermatitis where a positive correlation between increased TSLP expression and the aggravation of atopic dermatitis and lung inflammation has been shown [13, 14]. Previous works showed that TSLP expression is upregulated following exposure CHIR-99021 purchase to different factors including inflammatory mediators,

TLR activation and/or tissue damage by a NF-κB dependent mechanism [15, 16]. In addition, it has been demonstrated that the MAPK pathway is also involved in the regulation of TSLP expression in response to IL-1 and PMA-mediated signaling [17, 18]. This infers that both NF-κB and MAPK pathways cooperate in regulating TSLP expression. The role of TSLP in the gut is less extensively studied. Thus far, it has been shown that TSLP is constitutively expressed IMP dehydrogenase in IECs from healthy subjects, where it inhibits IL-12 production by DCs in response to bacteria, but not in cells from patients with chronic inflammation caused by active Crohn’s disease [5]. The aim of this work was to investigate the transcriptional regulation of the TSLP gene in the gut using IEC lines, HT-29, and Caco-2. We examined a 4 kb region of the human TSLP promoter and identified a number of putative NF-κB and AP-1 binding sites. We demonstrated that the NF-κB site located at –370 bp from the ATG (isoform 1) is the key site for IL-1-mediated transcriptional activation of TSLP in the IECs. Further analysis of other epithelial cell models (A549, HEK293, HeLa) confirmed the absolute requirement of this proximal NF-κB binding site for the NF-κB-dependent activation of TSLP gene transcription in epithelial cells. This work has revealed an important cell-specific aspect in the regulation of TSLP in epithelial cells.