The dual role of interleukin-6 in Crohn’s disease pathophysiology

Alhendi, Ala’; Naser, Saleh A.

doi:10.3389/fimmu.2023.1295230

Cited by 6 publications

(1 citation statement)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The enrichment of BP terms like Cytokine Production and Regulation of Cytokine Production suggest a possible central role of cytokine networks in CD pathophysiology. Such networks facilitate cell communication during immune responses (Alhendi A, Naser S, 2023;Vebr M et al, 2023).…”

Section: Genetic Associations In CD (Ibd)mentioning

confidence: 99%

Genetic Overlap Between Inflammatory Bowel Disease and Neurological Disorders: Insights from GWAS and Gene Expression Analysis

Tripathi,

Stern,

Dagan

et al. 2024

Preprint

View full text Add to dashboard Cite

Inflammatory Bowel Disease (IBD), which includes Crohn’s disease (CD) and Ulcerative Colitis (UC), is a complex and multifactorial condition marked by chronic inflammation of the gastrointestinal tract. This study leverages genome-wide association studies (GWAS) and gene expression data from the Genotype-Tissue Expression (GTEx) project to investigate IBD’s genetic and expression profiles and subtypes. We examined 207 studies related to IBD, 71 specific to CD, and 66 focused on UC, identifying both shared and unique genetic factors among these conditions. GWAS meta-analysis revealed the top IBD-associated genes, which include IL23R, NOD2, ATG16L1, HLA-DRB9, and more. Pathway enrichment analyses identified consistently enriched pathways such as the NF-kappa B signaling pathway, JAK-STAT signaling pathway, and cytokine-cytokine receptor interaction, all of which play critical roles in immune responses and inflammation. Gene Ontology (GO) term analysis highlighted processes like cytokine production, cell activation, and leukocyte activation, reinforcing their involvement in the pathogenesis of IBD. Gene expression analysis showed that genes associated with IBD are expressed not only in the gastrointestinal tract but also in various regions of the brain, suggesting potential links between IBD and neurological functions. Our study further explored the genetic overlap between IBD and several neurological disorders, including schizophrenia, depression, autism spectrum disorder, and attention-deficit/hyperactivity disorder, uncovering a shared genetic architecture. These findings emphasize the systemic nature of IBD and its potential neurological implications, paving the way for targeted therapeutic strategies that address both gastrointestinal and neurological aspects of the disease.

show abstract

Section: Genetic Associations In CD (Ibd)mentioning

confidence: 99%

Genetic Overlap Between Inflammatory Bowel Disease and Neurological Disorders: Insights from GWAS and Gene Expression Analysis

Tripathi,

Stern,

Dagan

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Identification of TIMP1-induced dysregulation of epithelial-mesenchymal transition as a key pathway in inflammatory bowel disease and small intestinal neuroendocrine tumors shared pathogenesis

Tran

2024

Front. Genet.

View full text Add to dashboard Cite

Inflammatory Bowel Disease (IBD) is believed to be a risk factor for Small Intestinal Neuroendocrine Tumors (SI-NET) development; however, the molecular relationship between IBD and SI-NET has yet to be elucidated. In this study, we use a systems biology approach to uncover such relationships. We identified a more similar transcriptomic-wide expression pattern between Crohn’s Disease (CD) and SI-NET whereas a higher proportion of overlapping dysregulated genes between Ulcerative Colitis (UC) and SI-NET. Enrichment analysis indicates that extracellular matrix remodeling, particularly in epithelial-mesenchymal transition and intestinal fibrosis mediated by TIMP1, is the most significantly dysregulated pathway among upregulated genes shared between both IBD subtypes and SI-NET. However, this remodeling occurs through distinct regulatory molecular mechanisms unique to each IBD subtype. Specifically, myofibroblast activation in CD and SI-NET is mediated through IL-6 and ciliary-dependent signaling pathways. Contrarily, in UC and SI-NET, this phenomenon is mainly regulated through immune cells like macrophages and the NCAM signaling pathway, a potential gut-brain axis in the context of these two diseases. In both IBD and SI-NET, intestinal fibrosis resulted in significant metabolic reprogramming of fatty acid and glucose to an inflammatory- and cancer-inducing state. This altered metabolic state, revealed through enrichment analysis of downregulated genes, showed dysfunctions in oxidative phosphorylation, gluconeogenesis, and glycogenesis, indicating a shift towards glycolysis. Also known as the Warburg effect, this glycolytic switch, in return, exacerbates fibrosis. Corresponding to enrichment analysis results, network construction and subsequent topological analysis pinpointed 7 protein complexes, 17 hub genes, 11 microRNA, and 1 transcription factor related to extracellular matrix accumulation and metabolic reprogramming that are candidate biomarkers in both IBD and SI-NET. Together, these biological pathways and candidate biomarkers may serve as potential therapeutic targets for these diseases.

show abstract

In vitro neutralization of IL-6 receptor exacerbates damage to intestinal epithelial cells during Mycobacterium avium paratuberculosis infection

Alhendi,

Naser

2024

Front. Immunol.

View full text Add to dashboard Cite

Like TNFα, IL-6 is upregulated in Crohn’s disease (CD) especially in patients associated with Mycobacterium avium paratuberculosis (MAP) infection, and both cytokines have been targeted as a therapeutic option for the treatment of the disease despite the accepted partial response in some patients. Limited response to anti-IL-6 receptor-neutralizing antibodies therapy may be related to the homeostatic dual role of IL-6. In this study, we investigated the effects and the signaling mechanism of IL-6 involved in intestinal epithelial integrity and function during MAP infection using an in vitro model that consists of THP-1, HT-29 and Caco-2 cell lines. Clinically, we determined that plasma samples from MAP-infected CD patients have higher IL-6 levels compared to controls (P-value < 0.001). In CD-like macrophages, MAP infection has significantly upregulated the secretion of IL-6 and the shedding of (IL-6R) from THP-1 macrophages, P-value < 0.05. Intestinal cell lines (Caco-2 and HT-29) were treated with the supernatant of MAP-infected THP-1 macrophages with or without a neutralizing anti-IL-6R antibody. Treating intestinal Caco-2 cells with supernatant of MAP-infected macrophages resulted in significant upregulation of intestinal damage markers including claudin-2 and SERPINE1/PAI-1. Interestingly, blocking IL-6 signaling exacerbated that damage and further increased the levels of the damage markers. In HT-29 cells, MAP infection upregulated MUC2 expression, a protective response that was reversed when IL-6R was neutralized. More importantly, blocking IL-6 signaling during MAP infection rescued damaged Caco-2 cells from MAP-induced apoptosis. The data clearly supports a protective role of IL-6 in intestinal epithelia integrity and function especially in CD patients associated with MAP infection. The findings may explain the ineffective response to anti-IL6 based therapy and strongly support a therapeutic option that restores the physiologic level of IL-6 in patient’s plasma. A new treatment strategy based on attenuation of IL-6 expression and secretion in inflammatory diseases should be considered.

show abstract

The dual role of interleukin-6 in Crohn’s disease pathophysiology

Cited by 6 publications

References 66 publications

Genetic Overlap Between Inflammatory Bowel Disease and Neurological Disorders: Insights from GWAS and Gene Expression Analysis

Genetic Overlap Between Inflammatory Bowel Disease and Neurological Disorders: Insights from GWAS and Gene Expression Analysis

Identification of TIMP1-induced dysregulation of epithelial-mesenchymal transition as a key pathway in inflammatory bowel disease and small intestinal neuroendocrine tumors shared pathogenesis

In vitro neutralization of IL-6 receptor exacerbates damage to intestinal epithelial cells during Mycobacterium avium paratuberculosis infection

Contact Info

Product

Resources

About