Bacterial flagellin is a dominant antigen in Crohn disease

Lodes, Michael J.; Cong, Yingzi; Elson, Charles O.; Mohamath, Raodoh; Landers, Carol J.; Targan, Stephan R.; Fort, Madeline M.; Hershberg, Robert M.

doi:10.1172/jci20295

Cited by 373 publications

(338 citation statements)

References 40 publications

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“…Activation of TLR5 by flagellin has been well established and growing evidence exists for the contribution of the flagellin/TLR5 complex in gastrointestinal disorders, like Crohn's Disease (CD) (Begue et al, 2006;Marx, 2007;Ramos et al, 2004). New types of flagellin molecules have been identified in CD patients (Elson et al, 2006;Lodes et al, 2004), while carriage of a TLR5-stop codon may provide protection against CD . The biological activity of flagellin, however, varies among bacterial species (Andersen-Nissen et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Ligand-induced differential cross-regulation of Toll-like receptors 2, 4 and 5 in intestinal epithelial cells

Aubel

Keestra

Krooshoop

et al. 2007

Molecular Immunology

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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.

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Section: Discussionmentioning

confidence: 99%

Ligand-induced differential cross-regulation of Toll-like receptors 2, 4 and 5 in intestinal epithelial cells

Aubel

Keestra

Krooshoop

et al. 2007

Molecular Immunology

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“…A recent study has demonstrated that colitic animals and patients with Crohn's disease express serum reactivity against flagellin derived from commensal bacteria (15). The response to flagellin was directed against a specific peptide sequence derived from a limited array of bacterial species.…”

Section: Location Location Locationmentioning

confidence: 99%

TLR Signaling in the Gut in Health and Disease

Abreu

Fukata

Arditi

2005

The Journal of Immunology

528

382

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The human intestine has evolved in the presence of diverse enteric microflora. TLRs convert the recognition of pathogen-associated molecules in the gut into signals for anti-microbial peptide expression, barrier fortification, and proliferation of epithelial cells. Healing of injured intestinal epithelium and clearance of intramucosal bacteria require the presence of intact TLR signaling. Nucleotide oligomerization domain (Nod)1 and Nod2 are additional pattern recognition receptors that are required for defense against invasive enteric pathogens. Through spatial and functional localization of TLR and Nod molecules, the normal gut maintains a state of controlled inflammation. By contrast, patients with inflammatory bowel disease demonstrate inflammation in response to the normal flora. A subset of these patients carry polymorphisms in TLR and CARD15/NOD2 genes. A better understanding of the delicate regulation of TLR and Nod molecules in the gut may lead to improved treatment for enteric infections and idiopathic inflammatory bowel diseases.

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“…The TLRs, with the exception of TLR10, have been detected in primary intestinal epithelial cells (IECs) (13), but the role of TLRs on IECs is controversial. Although RakoffNahoum et al (14) has shown that persistent and basal TLR activation induced by commensal microflora plays a crucial role in the maintenance of intestinal epithelial homeostasis, experimental data from both human and animals suggest that abnormal TLR signaling may contribute to the disruption of epithelial homeostasis in human inflammatory bowel disease and other enteric bacterial infections (15)(16)(17)(18)(19). However, none of these studies provides direct evidence that TLR signaling breaks down epithelial homeostasis or provides an understanding of the mechanisms responsible.…”

mentioning

confidence: 99%

Recognition of Double-Stranded RNA by TLR3 Induces Severe Small Intestinal Injury in Mice

Zhou

Wei

Sun

et al. 2007

The Journal of Immunology

116

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The role of TLRs on intestinal epithelial cells (IECs) is controversial, and the mechanisms by which TLRs influence mucosal homeostasis are obscure. In this study, we report that genomic dsRNA from rotavirus, and its synthetic analog polyinosinic-polycytidylic acid (poly(I:C)), induce severe mucosal injury in the small intestine. Upon engaging TLR3 on IECs, dsRNA triggers IECs to secrete IL-15, which functions to increase the percentage of CD3+NK1.1+ intestinal intraepithelial lymphocytes (IELs) and enhances the cytotoxicity of IELs. Moreover, The CD3+NK1.1+ IELs are proved as CD8αα+ IELs. These results provide direct evidence that abnormal TLR3 signaling contributes to breaking down mucosal homeostasis and the first evidence of pathogenic effects mediated by CD8αα+ IELs. The data also suggest that genomic dsRNA may be involved in the pathogenesis of acute rotavirus gastroenteritis.

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Bacterial flagellin is a dominant antigen in Crohn disease

Cited by 373 publications

References 40 publications

Ligand-induced differential cross-regulation of Toll-like receptors 2, 4 and 5 in intestinal epithelial cells

Ligand-induced differential cross-regulation of Toll-like receptors 2, 4 and 5 in intestinal epithelial cells

TLR Signaling in the Gut in Health and Disease

Recognition of Double-Stranded RNA by TLR3 Induces Severe Small Intestinal Injury in Mice

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