The NF‐κB binding site located in the proximal region of the TSLP promoter is critical for TSLP modulation in human intestinal epithelial cells

Abstract

Thymic stromal lymphopoietin (TSLP) is constitutively secreted by intestinal epithelial cells. It regulates gut DCs, therefore, contributing to the maintenance of immune tolerance. In the present report, we describe the regulation of TSLP expression in intestinal epithelial cells and characterize the role of several NF-κB binding sites present on the TSLP promoter. TSLP expression can be stimulated by different compounds through activation of p38, protein kinase A, and finally the NF-κB pathway. We describe a new NF-κB binding element located at position -0.37 kb of the promoter that is crucial for the NF-κB-dependent regulation of TSLP. We showed that mutation of this proximal NF-κB site abrogates the IL-1β-mediated transcriptional activation of human TSLP in several epithelial cell lines. We also demonstrated that both p65 and p50 subunits are able to bind this new NF-κB binding site. The present work provides new insight into epithelial cell-specific TSLP regulation.

Lipopolysaccharide Attenuates Induction of Proallergic Cytokines, Thymic Stromal Lymphopoietin, and Interleukin 33 in Respiratory Epithelial Cells Stimulated with PolyI:C and Human Parechovirus

“…We found that dexamethasone and Bay 11-7082 inhibited TSLP and IL33 expression by downregulating IRF3 and NF-κB activities. Coincidentally, the essential roles of the IRF3 and NF-κB pathways in TSLP and IL-33 induction were demonstrated in other research models [(16, 71–75), Schuijs et al (76) #5788]. Moreover, we found that LPS-modulated IRF3 and NF-κB activation in the polyI:C or HPeV1/TLR3 axis could be the causal mechanism of hygiene hypothesis.…”

TNF-related apoptosis-inducing ligand (TRAIL) regulates midline-1, thymic stromal lymphopoietin, inflammation, and remodeling in experimental eosinophilic esophagitis

“…It has been shown, however, that the TSLP promoter contains several binding sites for the p65 subunit of NF-κB; a transcription factor shown to be TRAIL dependent in AAD [41] which we show is also repressed in the oesophagus of TRAIL−/− in the EoE model. It has also been shown that the subsequent expression of TSLP in intestinal epithelia cells is dependent on NF-κB [41]. Given NF-κB is upregulated in EoE patients [42], it is possible that TRAIL is a key regulator of TSLP through p65 activation and contributes to EoE most likely through basophil activation [25].…”

“…It is still unknown how TSLP is regulated by TRAIL in EoE, given that no link between TRAIL and TSLP was evident in models of AAD [29]. It has been shown, however, that the TSLP promoter contains several binding sites for the p65 subunit of NF-κB; a transcription factor shown to be TRAIL dependent in AAD [41] which we show is also repressed in the oesophagus of TRAIL−/− in the EoE model. It has also been shown that the subsequent expression of TSLP in intestinal epithelia cells is dependent on NF-κB [41].…”

The human gut microbiome as source of innovation for health: Which physiological and therapeutic outcomes could we expect?

“…Several promising screenings were already implemented such as models of gut epithelial layer integrity, inflammation, immune cell maturation and immune-modulation, cell differentiation and proliferation, metabolism regulations and hormone secretion. These gave rise to the identification of original mechanisms of action and a range of publications and patents [76,[78][79][80][81][82][83][84][85][86][87][88].…”