Human mucosa/submucosa interactions during intestinal inflammation: involvement of the enteric nervous system in interleukin-8 secretion

Tixier, Emmanuelle; Lalanne, Florent; Just, Ingo; Galmiche, Jean–Paul; Neunlist, Michel

doi:10.1111/j.1462-5822.2005.00596.x

Cited by 46 publications

(31 citation statements)

References 48 publications

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“…Similarly, purified C. difficile toxins induce the release of inflammatory cytokines from cultured intestinal epithelial cells. In particular, IL-8, a neutrophil chemoattractant known to be regulated by the p38 pathway, is highly induced by toxin exposure in vitro (16)(17)(18). These findings suggest that p38 kinase is a critical early driver of the neutrophilic inflammatory response (16,17).…”

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confidence: 69%

MAPK-Activated Protein Kinase 2 Contributes to Clostridium difficile-Associated Inflammation

et al. 2013

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Clostridium difficile infection (CDI) results in toxin-induced epithelial injury and marked intestinal inflammation. Fecal markers of intestinal inflammation correlate with CDI disease severity, but regulation of the inflammatory response is poorly understood. Previous studies demonstrated that C. difficile toxin TcdA activates p38 kinase in tissue culture cells and mouse ilium, resulting in interleukin-8 (IL-8) release. Here, we investigated the role of phosphorylated mitogen-activated protein kinase (MAPK)-activated protein kinase (MK2 kinase, pMK2), a key mediator of p38-dependent inflammation, in CDI. Exposure of cultured intestinal epithelial cells to the C. difficile toxins TcdA and TcdB resulted in p38-dependent MK2 activation. Toxininduced IL-8 and GRO␣ release required MK2 activity. We found that p38 and MK2 are activated in response to other actin-disrupting agents, suggesting that toxin-induced cytoskeleton disruption is the trigger for kinase-dependent cytokine response. Phosphorylated MK2 was detected in the intestines of C. difficile-infected hamsters and mice, demonstrating for the first time that the pathway is activated in infected animals. Furthermore, we found that elevated pMK2 correlated with the presence of toxigenic C. difficile among 100 patient stool samples submitted for C. difficile testing. In conclusion, we find that MK2 kinase is activated by TcdA and TcdB and regulates the expression of proinflammatory cytokines. Activation of p38-MK2 in infected animals and humans suggests that this pathway is a key driver of intestinal inflammation in patients with CDI.

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confidence: 69%

MAPK-Activated Protein Kinase 2 Contributes to Clostridium difficile-Associated Inflammation

et al. 2013

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“…The average concentration of IL-8 in the CDI-positive stools was significantly (P Ͻ 0.05) higher than that in the stools from CDI-negative patients and hospitalized patients without diarrhea. IL-8 is a chemoattractant involved in the recruitment of neutrophils to sites of infection and has been implicated to play a key role in the pathogenesis of CDI (16). Increased levels of IL-8 are associated with more severe forms of CDI (6).…”

Section: Discussionmentioning

confidence: 99%

Colonic Immunopathogenesis of Clostridium difficile Infections

Darkoh

Turnwald

Koo

et al. 2014

Clin Vaccine Immunol

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f There are major gaps in our understanding of the immunopathogenesis of Clostridium difficile infections (CDIs). In this study, 36 different biomarkers were examined in the stools of CDI and non-CDI patients using the Proteome Profiler human cytokine array assay and quantitative enzyme-linked immunosorbent assay. Diarrheal stools from patients with CDI (CDI-positive diarrheal stools) showed higher relative amounts of the following inflammatory markers than the diarrheal stools from CDI-negative patients (CDI-negative diarrheal stools): C5a, CD40L, granulocyte colony-stimulating factor, I-309, interleukin-13 (IL-13), IL-16, IL-27, monocyte chemoattractant protein 1, tumor necrosis factor alpha, and IL-8. IL-8 and IL-23 were present in a larger number of CDI-positive diarrheal stools than CDI-negative diarrheal stools. Th1 and Th2 cytokines were not significantly different between the CDI-positive and CDI-negative diarrheal stools. Lactoferrin and calprotectin concentrations were also higher in the CDI-positive diarrheal stools. Our results demonstrate that CDI elicits a proinflammatory host response, and we report for the first time that IL-23 is a major marker in CDI-positive diarrheal stools. IL-23 may explain the lack of a robust immunological response exhibited by a proportion of CDI patients and may relate to recurrence; the IL-23 levels induced during CDI in these patients may be inadequate to sustain the cellular immunity conferred by this cytokine in promoting the induction and proliferation of effector memory T cells.

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“…Recently, other IVOCs have also been described, composed of specimens of human colon taken downstream of the tumor, allowing the study of proinflammatory colonic immune responses in a context of depletion of IL-10, which regulates a complex ecosystem composed of bacteria, the intestinal epithelial barrier, and resident colitogenic cells (867,868). Specimens of mucosa and submucosa, either cocultured or cultured alone, have been used to investigate the effect of Clostridium difficile toxin B on IL-8 production via the IL-1␤-dependent pathway (869) and the activation of the VIPergic neurons (870). Recently, human tissue preparations consisting of separated serosa and circular muscle have been used to culture the mucosal and submucosal fragments.…”

Section: Discussionmentioning

confidence: 99%

Pathogenesis of Human Enterovirulent Bacteria: Lessons from Cultured, Fully Differentiated Human Colon Cancer Cell Lines

Moal

Servin

2013

Microbiol Mol Biol Rev

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SUMMARY Hosts are protected from attack by potentially harmful enteric microorganisms, viruses, and parasites by the polarized fully differentiated epithelial cells that make up the epithelium, providing a physical and functional barrier. Enterovirulent bacteria interact with the epithelial polarized cells lining the intestinal barrier, and some invade the cells. A better understanding of the cross talk between enterovirulent bacteria and the polarized intestinal cells has resulted in the identification of essential enterovirulent bacterial structures and virulence gene products playing pivotal roles in pathogenesis. Cultured animal cell lines and cultured human nonintestinal, undifferentiated epithelial cells have been extensively used for understanding the mechanisms by which some human enterovirulent bacteria induce intestinal disorders. Human colon carcinoma cell lines which are able to express in culture the functional and structural characteristics of mature enterocytes and goblet cells have been established, mimicking structurally and functionally an intestinal epithelial barrier. Moreover, Caco-2-derived M-like cells have been established, mimicking the bacterial capture property of M cells of Peyer's patches. This review intends to analyze the cellular and molecular mechanisms of pathogenesis of human enterovirulent bacteria observed in infected cultured human colon carcinoma enterocyte-like HT-29 subpopulations, enterocyte-like Caco-2 and clone cells, the colonic T84 cell line, HT-29 mucus-secreting cell subpopulations, and Caco-2-derived M-like cells, including cell association, cell entry, intracellular lifestyle, structural lesions at the brush border, functional lesions in enterocytes and goblet cells, functional and structural lesions at the junctional domain, and host cellular defense responses.

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Human mucosa/submucosa interactions during intestinal inflammation: involvement of the enteric nervous system in interleukin-8 secretion

Cited by 46 publications

References 48 publications

MAPK-Activated Protein Kinase 2 Contributes to Clostridium difficile-Associated Inflammation

MAPK-Activated Protein Kinase 2 Contributes to Clostridium difficile-Associated Inflammation

Colonic Immunopathogenesis of Clostridium difficile Infections

Pathogenesis of Human Enterovirulent Bacteria: Lessons from Cultured, Fully Differentiated Human Colon Cancer Cell Lines

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