Metalloproteinases in Inflammatory Bowel Diseases

Marônek, Martin; Marafini, Irene; Gardlík, Roman; Link, Rene; Troncone, Edoardo; Monteleone, Giovanni

doi:10.2147/jir.s288280

Cited by 38 publications

(35 citation statements)

References 67 publications

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“…We further found that IL-26 can promote the mRNA and protein expression of MMP-8 and MMP-9 while inhibiting the expression of MMP-1 ( Figure 6 ). The overexpression of MMP-1, MMP-8, and MMP-9 is observed in the intestinal mucosa of IBD patients ( 48 ). MMP-9 has been implicated in the breakdown of intestinal epithelial barriers, and infiltrating macrophages are its primary producers in IBD ( 49 , 50 ).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-26 Expression in Inflammatory Bowel Disease and Its Immunoregulatory Effects on Macrophages

Song

Lai

et al. 2022

Front. Med.

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Background and AimInterleukin-26 (IL-26) has been implicated in several chronic inflammatory diseases. However, its role in inflammatory bowel disease (IBD) remains to be elucidated. We aimed to investigate IL-26 expression in IBD and its immunoregulatory effects on macrophages.MethodsWe assessed IL-26 expression in the intestinal mucosa and blood samples of IBD patients and healthy controls (HC). The associations between the clinical characteristics of IBD and IL-26 expression levels in serum and peripheral blood mononuclear cells (PBMCs) were investigated. In addition, the transcriptional changes in THP-1 macrophages exposed to IL-26 were determined by RNA sequencing and validated with qRT-PCR, ELISA and western blots.ResultsCompared with HC, in IBD patients, IL-26 expression levels were elevated in the inflamed intestinal mucosa, and reduced in serum and PBMCs. IL-26 mRNA levels in PBMCs, but not serum IL-26 levels, were inversely correlated with disease activity in IBD. Furthermore, IL-26 mRNA levels in PBMCs were significantly lower in patients with complicated Crohn’s disease. A total of 1,303 differentially expressed protein-coding genes were identified between untreated and IL-26-treated macrophages. The up-regulated genes showed enrichment in some inflammatory and immune-related processes and pathways. Additionally, GSEA showed that neutrophil, monocyte, and lymphocyte chemotaxis was significantly enriched in IL-26-treated macrophages. Further validation revealed that IL-26 promotes the secretion of multiple inflammatory cytokines and chemokines and upregulates the expression of adhesion molecules, MMP-8, and MMP-9 while inhibiting MMP-1 in macrophages.ConclusionCompared with HC, in IBD patients, IL-26 levels were elevated in the inflamed intestinal mucosa, and reduced in the peripheral blood. The transcriptional changes in macrophages exposed to IL-26 suggest that IL-26 may amplify the aberrant immune response in IBD by activating macrophages.

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Section: Discussionmentioning

confidence: 99%

Interleukin-26 Expression in Inflammatory Bowel Disease and Its Immunoregulatory Effects on Macrophages

Song

Lai

et al. 2022

Front. Med.

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“…Levels of inflammatory proteases are elevated in the inflamed mucosa of IBD patients 37 . In particular, activated matrix metalloproteinases (MMPs), such as MMP3 and MMP12 are abundant in these tissues 38,39 . These MMPs exhibit proteolytic activity on a broad range of protein substrates, including native IgG, therapeutic monoclonal antibodies and biologics that contain a human Fc scaffold, such as the TNFα inhibitor etanercept 35 .…”

Section: Resultsmentioning

confidence: 99%

Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease

Cubitt

Carlton

Rodrigues-Duarte

et al. 2021

Sci Rep

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Anti-TNFα and anti-IL-23 antibodies are highly effective therapies for Crohn’s disease or ulcerative colitis in a proportion of patients. V56B2 is a novel bispecific domain antibody in which a llama-derived IL-23p19-specific domain antibody, humanised and engineered for intestinal protease resistance, V900, was combined with a previously-described TNFα-specific domain antibody, V565. V56B2 contains a central protease-labile linker to create a single molecule for oral administration. Incubation of V56B2 with trypsin or human faecal supernatant resulted in a complete separation of the V565 and V900 monomers without loss of neutralising potency. Following oral administration of V900 and V565 in mice, high levels of each domain antibody were detected in the faeces, demonstrating stability in the intestinal milieu. In ex vivo cultures of colonic biopsies from IBD patients, treatment with V565 or V900 inhibited tissue phosphoprotein levels and with a combination of the two, inhibition was even greater. These results support further development of V56B2 as an oral therapy for IBD with improved safety and efficacy in a greater proportion of patients as well as greater convenience for patients compared with traditional monoclonal antibody therapies.

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“…MMPs are produced in excess in inflamed intestinal tissues of IBD patients and causes mucosal degradation ( 33 ). Recent study showed that MMP12 mediated the degradation of basement membrane laminin and the transmigration across intestinal epithelial tight junctions of macrophages, and increased severity of DSS-induced colitis of mice ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

EpCAM Is Essential to Maintaining the Immune Homeostasis of Intestines via Keeping the Expression of pIgR in the Intestinal Epithelium of Mice

et al. 2022

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EpCAM deficiency causes congenital tufting enteropathy (CTE) which is considered as one kinds of very early onset inflammatory bowel disease (IBD). However, functions of EpCAM on regulating the immunity of intestines are still unclear. To study the mechanism of EpCAM on maintaining the intestinal immune homeostasis, the intestines of WT and EpCAM-/- mice at E18.5, P0 and P3 stages were collected for morphological, histological and gene expression tests. Serious inflammation was detected in the small intestines of P3 EpCAM-/- mice. Compared to WT mice, genes related to inflammatory factors and immunity cells, including TNFα, IL-1β, IL-6, IL-8rb, MIP2, MCP1, Ly6d and Ly6g, were all significantly upregulated and the expression of intestinal abundance matrix metalloproteinases (MMPs) was also significantly increased in the intestines of EpCAM-/- mice at E18.5, P0 and P3 stages. Signals of p38, ERK1/2 and JNK were hyper-activated in the intestines of EpCAM-/- mice. The expression of pIgR was significantly decreased and the expression and activation of transcriptional factors which promote the expression of pIgR were also reduced in the intestines of EpCAM-/- mice compared to WT controls. In conclusion, EpCAM could maintain the immune homeostasis of intestines via keeping the expression of pIgR in the intestinal epithelium.

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Metalloproteinases in Inflammatory Bowel Diseases

Cited by 38 publications

References 67 publications

Interleukin-26 Expression in Inflammatory Bowel Disease and Its Immunoregulatory Effects on Macrophages

Interleukin-26 Expression in Inflammatory Bowel Disease and Its Immunoregulatory Effects on Macrophages

Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease

EpCAM Is Essential to Maintaining the Immune Homeostasis of Intestines via Keeping the Expression of pIgR in the Intestinal Epithelium of Mice

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