Role of EHEC O157:H7 virulence factors in the activation of intestinal epithelial cell NF-κB and MAP kinase pathways and the upregulated expression of interleukin 8

Berin, M. Cecilia; Darfeuille‐Michaud, Arlette; Egan, Laurence J.; Miyamoto, Yukiko; Kagnoff, Martin F.

doi:10.1046/j.1462-5822.2002.00218.x

Cited by 137 publications

(137 citation statements)

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“…These earlier studies found that purified EPEC flagellin induces IL-8 expression in IEC (47), while similar findings were made with EHEC flagellin (4). While these studies correctly highlighted the importance of EPEC flagellin as the major proinflammatory bacterial product within the supernatant, it has remained unclear whether A/E pathogens can cause significant inflammatory responses from epithelial cells in the absence of flagellin expression.…”

Section: Discussionmentioning

confidence: 73%

“…The next study examined which signaling pathways were involved in the IL-8 response to infection by WT and ⌬fliC EPEC, focusing on p38 MAPK and NF-B activation. Previous studies had shown that purified A/E flagellin and bacterial supernatants containing flagellin activate both pathways (4). Using a rabbit polyclonal antibody that detected the active phosphorylated tyrosine and threonine p38 MAPK, EPEC infection was observed to cause significant activation of p38 MAPK after 2 h of infection ( Fig.…”

Section: Vol 76 2008 Epithelial Responses To Epec and C Rodentium mentioning

confidence: 84%

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Flagellin-Dependent and -Independent Inflammatory Responses following Infection by EnteropathogenicEscherichia coliandCitrobacter rodentium

Khan

Bouzari

et al. 2008

Infect Immun

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Enteropathogenic Escherichia coli (EPEC) and the murine pathogen Citrobacter rodentium belong to the attaching and effacing (A/E) family of bacterial pathogens. These noninvasive bacteria infect intestinal enterocytes using a type 3 secretion system (T3SS), leading to diarrheal disease and intestinal inflammation. While flagellin, the secreted product of the EPEC fliC gene, causes the release of interleukin 8 (IL-8) from epithelial cells, it is unclear whether A/E bacteria also trigger epithelial inflammatory responses that are FliC independent. The aims of this study were to characterize the FliC dependence or independence of epithelial inflammatory responses to direct infection by EPEC or C. rodentium. Following infection of Caco-2 intestinal epithelial cells by wild-type and ⌬fliC EPEC, a rapid activation of several proinflammatory genes, including those encoding IL-8, monocyte chemoattractant protein 1, macrophage inflammatory protein 3␣ (MIP3␣), and ␤-defensin 2, occurred in a FliC-dependent manner. These responses were accompanied by mitogen-activated protein kinase activation, as well as the Toll-like receptor 5 (TLR5)-dependent activation of NF-B. At later infection time points, a subset of these proinflammatory genes (IL-8 and MIP3␣) was also induced in cells infected with ⌬fliC EPEC. The nonmotile A/E pathogen C. rodentium also triggered similar innate responses through a TLR5-independent but partially NF-B-dependent mechanism. Moreover, the EPEC FliC-independent responses were increased in the absence of the locus of enterocyte effacement-encoded T3SS, suggesting that translocated bacterial effectors suppress rather than cause the FliC-independent inflammatory response. Thus, we demonstrate that infection of intestinal epithelial cells by A/E pathogens can trigger an array of proinflammatory responses from epithelial cells through both FliC-dependent and -independent pathways, expanding our understanding of the innate epithelial response to infection by these pathogens.

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Section: Discussionmentioning

confidence: 73%

Section: Vol 76 2008 Epithelial Responses To Epec and C Rodentium mentioning

confidence: 84%

Flagellin-Dependent and -Independent Inflammatory Responses following Infection by EnteropathogenicEscherichia coliandCitrobacter rodentium

Khan

Bouzari

et al. 2008

Infect Immun

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“…Furthermore, Singer and Sansonetti (46) demonstrated that intraluminal addition of recombinant IL-8 was directly associated with the development of acute invasive Shigella-induced colitis. Berin et al (8) reported that enterohemorrhagic Escherichia coli O157:O7 (EHEC) infection of human intestinal epithelial cells activates MAP kinase and NF-B signaling pathways, thereby activating the expression and production of IL-8 in human intestinal epithelial cells (8,54,56). Ju et al (27) have shown that in gastric cancer IL-8 mediates cell migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc

Liu

Patel

Walter

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Liu H, Patel NR, Walter L, Ingersoll S, Sitaraman SV, Garg P. Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc. Am J Physiol Gastrointest Liver Physiol 304: G793-G803, 2013. First published March 7, 2013 doi:10.1152/ajpgi.00249.2012.-Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic inflammatory disease associated with an increased risk for colon cancer. Matrix metalloproteinases (MMPs) are the predominant proteinases expressed in the gut mucosa during active IBD. Our laboratory has previously demonstrated that epithelial-derived MMP9 is absent in normal colonic tissue but is upregulated during IBD. In this study MMP9 transgenic mice (Tg-villin-MMP9) are generated specifically to overexpress MMP9 in intestinal epithelium to examine the role and underlying mechanism by which it modulates the pathogenesis of acute colitis. Dextran sodium sulfate (3% DSS)-and Salmonella typhimurium (S.T.)-induced colitis models were used to study gut inflammation in Tg-villin-MMP9 and wild-type littermates (WT). Colonic tissue was analyzed via Western blot, histology, myeloperoxidase (MPO) assay, and quantitative PCR. Tg-villin-MMP9 mice expressed significantly increased MMP9 mRNA and protein expression at basal level. There was a significant decrease in the goblet cells, but a significant increase in proliferation and apoptosis were observed among Tg-villin-MMP9 mice compared with WT mice. There was also a significant increase in the proinflammatory chemokine Kc among Tg-villin-MMP9 compared with WT mice. Tg-villin-MMP9 exhibited a severe inflammatory response than WT mice in both DSSand S.T.-induced colitis models as evident by greater weight loss and higher clinical score, histological score, and MPO activity, which correlated with relative levels of Kc mRNA. MMP9 expressed by intestinal epithelial cells mediates inflammation in colitis with simultaneous increase in proinflammatory cytokine Kc. inflammation; dextran sodium sulfate; transgenic mice; IL-8 INFLAMMATORY BOWEL DISEASE (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammatory disease that affects the entire gastrointestinal (GI) tract and the colonic mucosa and is associated with an increased risk for colon cancer. IBD is characterized by relapses (acute flare) and remissions, which are related to genetic basis and involve immune-mediated tissue injury followed by repair. Recent studies have shown that cytokines play a key role in regulating IBD (9, 40). There is increased incidence of IBD in urban areas of industrialized nations (29,42). Matrix metalloproteinases (MMPs) are a group of zinc-dependent enzymes with proteolytic activity against extracellular matrix (ECM) proteins and are also known to play an important role for normal tissue remodeling (47). MMPs have also been shown to be involved in several pathological conditions such as IBD, tumor invasion, and colorect...

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“…The cells were seeded at a density of 2310 5 /well in 24-well plates at 37 uC in 5% CO 2 . For the IL-8 and MCP-1 release assays, Caco-2 cells were generally used 7 days later.…”

Section: Mcp-1 and Il-8 Releasing Assaysmentioning

confidence: 99%

“…2,3 TLR5 detects flagellin at the cell surface and signals through MyD88, resulting in the induction of proinflammatory cytokines, chemokines, antimicrobial defenses and antiapoptotic effects. [4][5][6] NAIP5/NLRC4 senses flagellin in the cytosol and activates caspase-1, which leads to the secretion of the pro-inflammatory cytokine, IL-1b 7 and pyroptotic cell death. 8 Flagellin contains two highly conserved N/C domains (D0 and D1) and one central hypervariable domain (D2/D3).…”

Section: Introductionmentioning

confidence: 99%

Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice

et al. 2014

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Flagellin is a potent activator of a broad range of cell types that are involved in innate and adaptive immunity. Therefore, it is a good adjuvant candidate for vaccines, and it might function as a biological protectant against both major acute radiation syndrome during cancer radiotherapy and a mitigator of radiation emergencies. However, accumulating evidence has implicated flagellin in the occurrence of some inflammatory diseases, such as acute lung inflammation, cardiovascular collapse and inflammatory bowel disease. The aim of this study was to elucidate whether only flagellin-TLR5 signaling activation plays a role in the pathophysiology of liver or whether some other flagellin activity also contributes to liver injury either via bacterial infections or during clinical applications. Recombinant flagellin proteins with or without TLR5-stimulating activity were used to evaluate the role of flagellin-TLR5 signaling in liver injury in wild-type and TLR5 KO mice. Gross lesions and large areas of hepatocellular necrosis were observed in liver tissue 12 h after the intraperitoneal administration of 100 or 200 mg flagellin (FliC) in a dose-and time-dependent manner in wild-type mice, but not in TLR5 KO mice. Deletion of the N-terminal or TLR5 binding domain of flagellin inhibited flagellin-induced inflammatory responses and the subsequent acute liver function abnormality and damage. These data confirmed that flagellin is an essential determinant of liver injury and demonstrated that the over-activation of TLR5 signaling by high-dose flagellin caused acute inflammatory responses, neutrophil accumulation and oxidative stress in the liver, which contributes to the progression and severity of flagellin-induced liver injury.

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Role of EHEC O157:H7 virulence factors in the activation of intestinal epithelial cell NF-κB and MAP kinase pathways and the upregulated expression of interleukin 8

Cited by 137 publications

References 53 publications

Flagellin-Dependent and -Independent Inflammatory Responses following Infection by EnteropathogenicEscherichia coliandCitrobacter rodentium

Flagellin-Dependent and -Independent Inflammatory Responses following Infection by EnteropathogenicEscherichia coliandCitrobacter rodentium

Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc

Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice

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