Enhanced Expression of CXCL10 in Inflammatory Bowel Disease

Østvik, Ann Elisabet; Granlund, Atle van Beelen; Bugge, Marit; Nilsen, Nadra J.; Torp, Sverre Helge; Waldum, Helge L.; Damås, Jan Kristian; Espevik, Terje; Sandvik, Arne K.

doi:10.1002/ibd.23034

Cited by 63 publications

(37 citation statements)

References 31 publications

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“…Therefore, enterocytes are active producers of CXCL10 in the duodenum of CD patients during the inflammatory process, and this production of CXCL10 is triggered by gluten intake. Although this study provides the first demonstration of the production of CXCL10 by enterocytes in the small intestine, similar results have been described in the colon [32], [33], and recently, the upregulation of CXCL10 was observed in colonic enterocytes in inflammatory bowel diseases [9]. Altogether, these findings indicate that enterocytes actively produce CXCL10 in a chronic inflammatory setting.…”

Section: Discussionsupporting

confidence: 89%

Role of CXCR3/CXCL10 Axis in Immune Cell Recruitment into the Small Intestine in Celiac Disease

et al. 2014

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Lymphocytic infiltration in the lamina propria (LP), which is primarily composed of CD4+ Th1 cells and plasma cells, and increased numbers of intraepithelial lymphocytes (IELs), is a characteristic finding in active celiac disease (CD). Signals for this selective cell recruitment have not been fully established. CXCR3 and its ligands, particularly CXCL10, have been suggested to be one of the most relevant pathways in the attraction of cells into inflamed tissues. In addition, CXCR3 is characteristically expressed by Th1 cells. The aim of this work was to investigate the participation of the chemokine CXCL10/CXCR3 axis in CD pathogenesis. A higher concentration of CXCL10 was found in the serum of untreated CD patients. The mRNA levels of CXCL10 and CXCL11 but not CXCL9 were significantly higher in duodenal biopsies from untreated CD patients compared with non-CD controls or treated patients. The results demonstrate that CXCL10 is abundantly produced in untreated CD and reduced in treated patients, and the expression of CXCL10 was found to be correlated with the IFNγ levels in the tissue. Plasma cells and enterocytes were identified as CXCL10-producing cells. Moreover, the CXCL10 expression in intestinal tissues was upregulated by poly I:C and IL-15. IELs, LP T lymphocytes, and plasma cells, which infiltrate the intestinal mucosa in untreated CD, express CXCR3. The CXCR3/CXCL10 signalling axis is overactivated in the small intestinal mucosa in untreated patients, and this finding explains the specific recruitment of the major cell populations that infiltrate the epithelium and the LP in CD.

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Section: Discussionsupporting

confidence: 89%

Role of CXCR3/CXCL10 Axis in Immune Cell Recruitment into the Small Intestine in Celiac Disease

et al. 2014

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“…21–24 IL-8 is a chemo attractant that induces neutrophil chemo taxis and phagocytosis, and IP-10 is a chemokine that attracts inflammatory cells. 25–29 MMP-3 degrades extracellular matrix under inflammatory conditions, 14 and S100-A8 is a subunit of cal protect in, a biomarker for fecal inflammation, that is used to monitor disease activity in inflammatory bowel disease. 16, 30, 31 …”

Section: Methodsmentioning

confidence: 99%

Validation of Gene Expression Biomarker Analysis for Biopsy-based Clinical Trials in Crohnʼs Disease

Boland

Boyle

Sandborn

et al. 2015

Inflammatory Bowel Diseases

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Background The ability to measure the expression of pro-inflammatory cytokines from intestinal biopsies in patients with Crohn’s disease in an accurate and reproducible way is critical for proof-of-concept and mechanism-of-action trials; however, the number of biopsies from a segment of the ileum or colon required to yield reproducible results has not been rigorously evaluated. We examined intestinal biopsies from patients with Crohn’s disease to validate methods for detecting changes in inflammatory gene expression. Methods To evaluate the reproducibility of gene expression measurements, intestinal biopsies were obtained from designated segmentsfrom6 healthy controls, 6 patients with active Crohn’s disease, and 6 patients with inactive Crohn’s disease. Disease activity was based on the simple endoscopic score for Crohn’s disease (SES-CD). Expression of 7 pro-inflammatory genes was measured from each biopsy using quantitative PCR. Using a linear mixed effects model, the power to detect transcriptional changes corresponding to active and inactive Crohn’s disease was calculated. Results Total SES-CD score corresponds with expression of most inflammatory biomarkers. For most genes, 2 – 5biopsies are needed to reduce sampling error to <25% for most genes. To measure changes in mRNA expression corresponding to active versus inactive Crohn’s disease, one to two intestinal biopsies from 3 patients before and after treatment are needed to yield power of at least 80%. Conclusion Measuring pro-inflammatory gene expression from mucosal biopsies from patients with Crohn’s disease is practicable and provides objective biomarkers that can be utilized in proof-of-concept and mechanism-of-action trials to assess response to therapy.

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“…Elevated amounts of LCN2 have been detected in mice fed a high-fat, high-salt diet and in colitis models (5). Recent studies of patients with IBD showed that LCN2 was among the 10 most upregulated genes in both active ulcerative colitis and active Crohn's disease compared with healthy controls (192). LCN2 protein was found in both epithelial cells and infiltrating neutrophils, whereas mRNA synthesis was detected only in epithelial cells.…”

Section: Biomarkers Of Intestinal Epithelial Permeability and Integrimentioning

confidence: 99%

Homeostasis of the gut barrier and potential biomarkers

Wells

Brummer

Derrien

et al. 2017

American Journal of Physiology-Gastrointestinal and Liver Physi

475

377

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The gut barrier plays a crucial role by spatially compartmentalizing bacteria to the lumen through the production of secreted mucus and is fortified by the production of secretory IgA (sIgA) and antimicrobial peptides and proteins. With the exception of sIgA, expression of these protective barrier factors is largely controlled by innate immune recognition of microbial molecular ligands. Several specialized adaptations and checkpoints are operating in the mucosa to scale the immune response according to the threat and prevent overreaction to the trillions of symbionts inhabiting the human intestine. A healthy microbiota plays a key role influencing epithelial barrier functions through the production of short-chain fatty acids (SCFAs) and interactions with innate pattern recognition receptors in the mucosa, driving the steady-state expression of mucus and antimicrobial factors. However, perturbation of gut barrier homeostasis can lead to increased inflammatory signaling, increased epithelial permeability, and dysbiosis of the microbiota, which are recognized to play a role in the pathophysiology of a variety of gastrointestinal disorders. Additionally, gut-brain signaling may be affected by prolonged mucosal immune activation, leading to increased afferent sensory signaling and abdominal symptoms. In turn, neuronal mechanisms can affect the intestinal barrier partly by activation of the hypothalamus-pituitary-adrenal axis and both mast cell-dependent and mast cell-independent mechanisms. The modulation of gut barrier function through nutritional interventions, including strategies to manipulate the microbiota, is considered a relevant target for novel therapeutic and preventive treatments against a range of diseases. Several biomarkers have been used to measure gut permeability and loss of barrier integrity in intestinal diseases, but there remains a need to explore their use in assessing the effect of nutritional factors on gut barrier function. Future studies should aim to establish normal ranges of available biomarkers and their predictive value for gut health in human cohorts.

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Enhanced Expression of CXCL10 in Inflammatory Bowel Disease

Cited by 63 publications

References 31 publications

Role of CXCR3/CXCL10 Axis in Immune Cell Recruitment into the Small Intestine in Celiac Disease

Role of CXCR3/CXCL10 Axis in Immune Cell Recruitment into the Small Intestine in Celiac Disease

Validation of Gene Expression Biomarker Analysis for Biopsy-based Clinical Trials in Crohnʼs Disease

Homeostasis of the gut barrier and potential biomarkers

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