Formed the experiments: AM FM. Analyzed the data: AM FM. Wrote the paper: AM FM SJT.
Innate immunity is central to host defense against invading pathogens, providing recognition of microorganisms and rapid deployment and activation of effector cells [1]. Activation of innate immunity also initiates subsequent adaptive immune responses. The ability to recognize microorganisms depends in part on a family of receptors known as the Toll-like receptors (TLRs) [1,2]. There are 13 known mammalian TLRs. Ligand engagement of TLR leads to activation of two pathways. TLR1, 2, 11967625 4, 5, 6, 7, 8, and 9 signal via the MyD88 adaptor, whereas TLR3 activates an alternative “MyD88-independent” pathway [1,2]. TLR4 is the only receptor known to activate both MyD88 dependent and independent pathways [1,2]. TLRs can be divided into two groups on the basis of their subcellular localization: TLR1, 2, 4, 5 and 6 are expressed on the surface of the cells and recognize lipid structures and in the case of TLR5, the protein flagellin. TLR3, 7, 8 and 9 all reside intracellularly and recognise nucleic acids. The localization and trafficking of TLRs within the cell is an important mechanism to allow TLRs to sense proper ligands and modulate downstream signaling [1,2]. A body of evidence support a mechanistic role ofTLR dysfunction in development of inflammatory bowel diseases (IBDs) [3]. Nuclear receptors are transcription factors highly expressed in entero-hepatic tissues integrating nutrient absorption, lipid and glucose metabolism, energy homeostasis, reproduction and development, and xenobiotic metabolism [4,5]. There is evidence that these transcription factors undergo gene regulation in response to the microbial flora residing in the gastrointestinal tract and that this changes contributes to local development and tuning of gut homeostasis in addition to driving maturation of the host adaptive immune system [6?]. Recent data suggest that nuclear receptors are regulated under intestinal inflammation [9,10]. This view emerges from the observation that while commensal bacteria elevate the expression of peroxisome proliferator-activated receptor (PPAR)c in colonic epithelial cells and can regulate intestinal inflammation by inhibiting NF-kB activity in a PPARc-dependent manner [11], inflammation induced in rodents or by IBDs associates with a robust downregulation of the expression of a number of nuclear receptors including PPARc, liver-x-receptor (LXRs), pregnane-xreceptor (PXR), farnesoid-x-receptor (FXR) and retinoid-x-receptor (RXR) among others [9]. Because these receptors exertFXR Is a Novel TLR-9 Target Genecounter-regulatory activities on macrophages and epithelial cells by inhibiting downstream targets of the TLR pathways [12,13], aberrations in their expression might have impact in the pathogenesis of human diseases. MedChemExpress LED 209 Further on, because nuclear receptors exert their regulatory effects beyond the intestinal wall, their dysregulation might have systemic effects. FXR is a bile acid sensor whose expression is highly restricted to entero-hepatic tissues [14]. FXR is required to maintain intestinal integrity and its deficiency results in altered intestinal permeability and tendency toward development of AKT inhibitor 2 site dysregulated immune response [15,16]. Despite a dysregulated expression of FXR has been linked to IBDs [17], the mechanisms that govern FXR expression in the intestine are poorly defined. In the present study we have investigated the mechanism of regulation of FXR b.Formed the experiments: AM FM. Analyzed the data: AM FM. Wrote the paper: AM FM SJT.
Innate immunity is central to host defense against invading pathogens, providing recognition of microorganisms and rapid deployment and activation of effector cells [1]. Activation of innate immunity also initiates subsequent adaptive immune responses. The ability to recognize microorganisms depends in part on a family of receptors known as the Toll-like receptors (TLRs) [1,2]. There are 13 known mammalian TLRs. Ligand engagement of TLR leads to activation of two pathways. TLR1, 2, 11967625 4, 5, 6, 7, 8, and 9 signal via the MyD88 adaptor, whereas TLR3 activates an alternative “MyD88-independent” pathway [1,2]. TLR4 is the only receptor known to activate both MyD88 dependent and independent pathways [1,2]. TLRs can be divided into two groups on the basis of their subcellular localization: TLR1, 2, 4, 5 and 6 are expressed on the surface of the cells and recognize lipid structures and in the case of TLR5, the protein flagellin. TLR3, 7, 8 and 9 all reside intracellularly and recognise nucleic acids. The localization and trafficking of TLRs within the cell is an important mechanism to allow TLRs to sense proper ligands and modulate downstream signaling [1,2]. A body of evidence support a mechanistic role ofTLR dysfunction in development of inflammatory bowel diseases (IBDs) [3]. Nuclear receptors are transcription factors highly expressed in entero-hepatic tissues integrating nutrient absorption, lipid and glucose metabolism, energy homeostasis, reproduction and development, and xenobiotic metabolism [4,5]. There is evidence that these transcription factors undergo gene regulation in response to the microbial flora residing in the gastrointestinal tract and that this changes contributes to local development and tuning of gut homeostasis in addition to driving maturation of the host adaptive immune system [6?]. Recent data suggest that nuclear receptors are regulated under intestinal inflammation [9,10]. This view emerges from the observation that while commensal bacteria elevate the expression of peroxisome proliferator-activated receptor (PPAR)c in colonic epithelial cells and can regulate intestinal inflammation by inhibiting NF-kB activity in a PPARc-dependent manner [11], inflammation induced in rodents or by IBDs associates with a robust downregulation of the expression of a number of nuclear receptors including PPARc, liver-x-receptor (LXRs), pregnane-xreceptor (PXR), farnesoid-x-receptor (FXR) and retinoid-x-receptor (RXR) among others [9]. Because these receptors exertFXR Is a Novel TLR-9 Target Genecounter-regulatory activities on macrophages and epithelial cells by inhibiting downstream targets of the TLR pathways [12,13], aberrations in their expression might have impact in the pathogenesis of human diseases. Further on, because nuclear receptors exert their regulatory effects beyond the intestinal wall, their dysregulation might have systemic effects. FXR is a bile acid sensor whose expression is highly restricted to entero-hepatic tissues [14]. FXR is required to maintain intestinal integrity and its deficiency results in altered intestinal permeability and tendency toward development of dysregulated immune response [15,16]. Despite a dysregulated expression of FXR has been linked to IBDs [17], the mechanisms that govern FXR expression in the intestine are poorly defined. In the present study we have investigated the mechanism of regulation of FXR b.