Time-course expression of Toll-like receptors 2 and 4 in inflammatory bowel disease and homeostatic effect of VIP (original) (raw)
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Effect of chemical modulation of toll-like receptor 4 in an animal model of ulcerative colitis
European Journal of Clinical Pharmacology, 2020
Purpose The partial ineffectiveness and side effects of inflammatory bowel disease (IBD) current therapies drive basic research to look for new therapeutic target in order to develop new drug lead. Considering the pivotal role played by toll-like receptors (TLRs) in gut inflammation, we evaluate here the therapeutic effect of the synthetic glycolipid TLR4 antagonist FP7. Methods The anti-inflammatory effect of FP7, active as TLR4 antagonist, was evaluated on peripheral blood mononuclear cells (PBMCs) and lamina propria mononuclear cells (LPMCs) isolated from IBD patients, and in a mouse model of ulcerative colitis. Results FP7 strongly reduced the inflammatory responses induced by lipopolysaccharide (LPS) in vitro, due to its capacity to compete with LPS for the binding of TLR4/MD-2 receptor complex thus inhibiting both the MyD88-and TRIF-dependent inflammatory pathways. Colitic mice treated with FP7 exhibit reduced colonic inflammation and decreased levels of proinflammatory cytokines. Conclusions This study suggests that TLR4 chemical modulation can be an effective therapeutic approach to IBD. The selectivity of FP7 on TLR4 makes this molecule a promising drug lead for new small molecules-based treatments.
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2004
The interleukin-2-deficient (IL-2−/−) mouse model of ulcerative colitis was used to test the hypothesis that colonic epithelial cells (CEC) directly respond to bacterial antigens and that alterations in Toll-like receptor (TLR)-mediated signaling may occur during the development of colitis. TLR expression and activation of TLR-mediated signaling pathways in primary CEC of healthy animals was compared with CEC in IL-2−/−mice during the development of colitis. In healthy animals, CEC expressed functional TLR, and in response to the TLR4 ligand LPS, proliferated and secreted the cytokines IL-6 and monocyte chemoattractant protein-1 (MCP-1). However, the TLR-responsiveness of CEC in IL-2−/−mice was different with decreased TLR4 responsiveness and augmented TLR2 responses that result in IL-6 and MCP-1 secretion. TLR signaling in CEC did not involve NF-κB (p65) activation with the inhibitory p50 form of NF-κB predominating in CEC in both the healthy and inflamed colon. Development of coli...
Clinical & Experimental Immunology, 2015
The innate immune system is currently seen as the probable initiator of events which culminate in the development of inflammatory bowel disease (IBD) with Toll-like receptors (TLRs) known to be involved in this disease process. Many regulators of TLRs have been described, and dysregulation of these may also be important in the pathogenesis of IBD. The aim of this study was to perform a coordinated analysis of the expression levels of both key intestinal TLRs and their inhibitory proteins in the same IBD cohorts, both ulcerative colitis (UC) and Crohn's disease (CD), in order to evaluate the potential roles of these proteins in the pathogenesis of IBD. Of the six TLRs (TLRs 1, 2, 4, 5, 6 and 9) examined, only TLR-4 was increased significantly in IBD, specifically in active UC. In contrast, differential alterations in expression of TLR inhibitory proteins were observed. A20 and suppressor of cytokine signalling 1 (SOCS1) were increased only in active UC while interleukin-1 receptor-associated kinase 1 (IRAK-m) and B cell lymphoma 3 protein (Bcl-3) were increased in both active UC and CD. In contrast, expression of both peroxisome proliferator-activated receptor gamma (PPARg) and Toll interacting protein (Tollip) was decreased in both active and inactive UC and CD and at both mRNA and protein levels. In addition, expression of both PPARg and A20 expression was increased by stimulation of a colonic epithelial cell line Caco-2 with both TLR ligands and commensal bacterial strains. These data suggest that IBD may be associated with distinctive changes in TLR-4 and TLR inhibitory proteins, implying that alterations in these may contribute to the pathogenesis of IBD.
Molecular Immunology, 2007
Toll-like receptors (TLR) 2, TLR4 and TLR5 are primary mucosal sensors of microbial patterns. Dissection of the cross-talk between TLRs in intestinal cells has thus far been hampered by the lack of functional TLR2 and TLR4 in in vitro model systems. Here we report that the mouse intestinal epithelial cell line mIC cl2 expresses these TLRs and that receptor expression and function are regulated by environmental TLR stimuli. Our results show that stimulation of TLR5 by bacterial flagellin resulted in upregulated TLR2 and TLR4 mRNA and concomitant sensitization of the cells for subsequent TLR2 (Pam 3 CSK 4 ) and TLR4 (LPS) stimulation. Exposure to low amounts of either Pam 3 CSK 4 or LPS in turn downregulated TLR5 mRNA and attenuated subsequent flagellin-mediated NF-B activation, pointing to a negative feedback mechanism. Pam 3 CSK 4 and LPS also downregulated TLR4 mRNA but upregulated TLR2 mRNA and sensitized cells for subsequent TLR2 stimulation. Inhibition of the phosphatidylinositol-3-kinase/Akt pathway only affected LPS-mediated TLR cross-talk indicating that differential TLR cross-regulation was conferred via different mechanisms. Together, our results demonstrate that the expression and function of TLR in intestinal cells are highly dynamic and tightly regulated in response to encountered bacterial stimuli.
Journal of Proteome Research, 2009
Toll-like receptors (TLRs) play an important role in the recognition of microbial molecular patterns of infectious and commensal bacteria and their expression in various tissues including the intestinal epithelium orchestration of the innate and adaptive immune defense mechanisms. Changes in the TLR signaling pathways due to host genetic predispositions may turn a physiological response into a pathological situation including failure of bacterial clearance and development of chronic inflammation. The aim of this study was to characterize the role of TLR2 or TLR4 deficiency in epithelial cell stress responses under noninflamed and inflamed conditions using TLR-deficient mice and TLR-/crossbred IL-10-deficient mice as a model for genetically driven experimental colitis. Primary intestinal epithelial cells (IEC) were isolated from specific-pathogen-free wild-type, TLR2-, TLR4-, IL-10-, IL-10XTLR2and IL-10XTLR4-deficient mice at the age of 1, 8, and 16 weeks. Histopathological analysis showed absence of tissue pathology (score 0-12) in distal colon sections of TLR2-and TLR4-deficient mice. In addition, TLR2-but not TLR4-deficient mice cross-bred to the IL-10-deficient background develop moderate colitis, suggesting different effects of these pattern recognition receptors in regulating disease mechanisms. Proteome analysis revealed significantly regulated proteins associated with endoplasmic reticulum (ER) and mitochondrial stress responses in the epithelium. In contrast to TLR2-/and IL-10XTLR2-/mice, the induction of the ER-associated chaperone grp-78 was dissociated from the activation of proapoptotic caspase 3 cleavage in noninflamed TLR4-/and IL10XTLR4-/mice. These results suggest that ER-associated cellular stress responses play an important role in epithelial cells homeostasis leading to beneficial but also deleterious effects. We hypothesize that ER stress-associated processes in the absence of TLR2 and TLR4 differentially affect host responses and epithelial functions under conditions of genetically driven chronic intestinal inflammation.
Clinical and Experimental Immunology, 2015
Summary The innate immune system is currently seen as the probable initiator of events which culminate in the development of inflammatory bowel disease (IBD) with Toll-like receptors (TLRs) known to be involved in this disease process. Many regulators of TLRs have been described, and dysregulation of these may also be important in the pathogenesis of IBD. The aim of this study was to perform a co-ordinated analysis of the expression levels of both key intestinal TLRs and their inhibitory proteins in the same IBD cohorts, both ulcerative colitis (UC) and Crohn's disease (CD), in order to evaluate the potential roles of these proteins in the pathogenesis of IBD. Of the six TLRs (TLRs 1, 2, 4, 5, 6 and 9) examined, only TLR-4 was increased significantly in IBD, specifically in active UC. In contrast, differential alterations in expression of TLR inhibitory proteins were observed. A20 and suppressor of cytokine signalling 1 (SOCS1) were increased only in active UC while interleukin-...