The Epithelial Danger Signal IL-1α Is a Potent Activator of Fibroblasts and Reactivator of Intestinal Inflammation

Scarpa, Melania; Kessler, Sean P.; Sadler, Tammy; West, Gail; Homer, Craig R.; McDonald, Christine; Motte, Carol de la; Fiocchi, Claudio; Stylianou, Eleni

doi:10.1016/j.ajpath.2015.02.018

Cited by 66 publications

(48 citation statements)

References 63 publications

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“…CTBp administration blunted the elevation of these markers, most notably IL-1a, which is a key factor to exacerbate gut inflammation. 30 Notably, CTBptreatment completely blocked the AOM/DSS-induced decrease of IFNg and IL-2 levels, which could be linked to the reduced tumorigenesis in this group. 31,32…”

Section: Ctbp Mitigates Dss-induced Acute Colonic Injury and Inflammamentioning

confidence: 77%

Oral administration of a recombinant cholera toxin B subunit promotes mucosal healing in the colon

et al. 2017

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Cholera toxin B subunit (CTB) is a component of a licensed oral cholera vaccine. However, CTB has pleiotropic immunomodulatory effects whose impacts on the gut are not fully understood. Here, we found that oral administration in mice of a plant-made recombinant CTB (CTBp) significantly increased several immune cell populations in the colon lamina propria. Global gene expression analysis revealed that CTBp had more pronounced impacts on the colon than the small intestine, with significant activation of TGFβ-mediated pathways in the colon epithelium. The clinical relevance of CTBp-induced impacts on colonic mucosa was examined. In a human colon epithelial model using Caco2 cells, CTBp, but not the non-GM1-binding mutant G33D-CTBp, induced TGFβ-mediated wound healing. In a dextran sodium sulfate (DSS) acute colitis mouse model, oral administration of CTBp protected against colon mucosal damage as manifested by mitigated body weight loss, decreased histopathological scores, and blunted escalation of inflammatory cytokine levels while inducing wound healing-related genes. Furthermore, biweekly oral administration of CTBp significantly reduced disease severity and tumorigenesis in the azoxymethane/DSS model of ulcerative colitis and colon cancer. Altogether, these results demonstrate CTBp's ability to enhance mucosal healing in the colon, highlighting its potential application in ulcerative colitis therapy besides cholera vaccination.

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Section: Ctbp Mitigates Dss-induced Acute Colonic Injury and Inflammamentioning

confidence: 77%

Oral administration of a recombinant cholera toxin B subunit promotes mucosal healing in the colon

et al. 2017

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“…Indeed, BM transplantation experiments have indicated that both IL-1α and IL-1β from later appearing BM infiltrating cells possibly amplify and sustain the inflammatory response. Others have also described the alarmin function of IEC-derived IL-1α in activation of colon myofibroblasts [145,146]. In contrast, IL-1β KO mice were much more susceptible to DSS-induced colitis, as seen by lower survival rates and manifestation of severe and non-healing tissue damage, with only a marginal inflammatory response, as compared to WT mice.…”

Section: Il-1 In Colon Inflammation and Carcinogenesismentioning

confidence: 99%

IL-1 in Colon Inflammation, Colon Carcinogenesis and Invasiveness of Colon Cancer

Voronov

Apte

2015

Cancer Microenvironment

100

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Interleukin-1 (IL-1) is a major "alarm" upstream pro-inflammatory cytokine that mainly acts by inducing cascades of cytokine and inflammation-promoting mediators. In the tumor arena, IL-1 is produced by both malignant and microenvironmental cells. IL-1α and IL-1β are the major agonists of IL-1, while IL-1Ra is a physiological inhibitor of pre-formed IL-1. IL-1α and IL-1β differ in their compartmentalization and in the producing cells. IL-1β is only active in its inflammasome dependent processed and secreted form and has been considered as the major mediator of inflammation. On the other hand, IL-1α is mainly cell-associated in tissue resident cells, being also active in its precursor form. The role of the IL-1 molecules in the unique microenvironment in the colon is largely unknown. Here, we described the role of IL-1α and IL-1β in colon homeostasis, colon inflammation, colon carcinogenesis and invasiveness of colorectal cancer. Understanding of the integrative role of IL-1α and IL-1β in these processes will facilitate the application of novel IL-1 modulating approaches.

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“…IL-1α is a key inflammatory mediator that serves an important role in early phases of IBD. Increased expression of IL-1α has been reported in experimental models of colitis and colon biopsies from IBD patients (26,27). It serves an Total nuclear proteins were extracted and nuclear NF-κB p65 was assayed in the lysate in colonic smooth muscle cells following treatment with LPS (1 µg/ml) and varying amounts of metformin (0, 5, 10 and 20 mM) * P<0.01 vs. the Ctrl group; # P<0.01 vs. the LPS group.…”

Section: Discussionmentioning

confidence: 99%

Metformin exerts anti‑inflammatory effects on mouse colon smooth muscle cells in�vitro

et al. 2018

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Inflammatory bowel disease (IBD) is a chronic incurable condition characterized by relapsing inflammation of the gut. Intestinal smooth muscle cells (SMCs) are affected structurally and functionally during IBD due to excessive production of different inflammatory mediators. Metformin is a widely used antidiabetic agent known to exert several anti-inflammatory effects in different tissues independently from its hypoglycemic effect. The aim of the present study was to investigate the effect of metformin on expression and secretion of different cytokines and chemokines from mouse colon SMCs (CSMCs) following induction of inflammation with lipopolysaccharide (LPS) . CSMCs from male BALB/c mice were isolated and cultured in Dulbecco's modified Eagle's medium and treated with LPS (1 µg/ml) and 0, 5, 10 or 20 mM metformin for 24 h. Expression and secretion of tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), macrophage colony stimulating factor (M-CSF), T cell activation gene-3 (TCA-3) and stromal cell-derived factor-1 (SDF-1) was evaluated by ELISA. LPS-treated CSMCs demonstrated significantly increased expression of TNF-α, IL-1α, M-CSF, TCA-3 and SDF-1 when compared with the control group (P<0.05). Co-treatment with metformin (5 and 10 mM) significantly reduced their expression by ~20-40% when compared with LPS treatment alone (P<0.05). Furthermore, secretion of TNF-α, IL-1α, M-CSF and TCA-3 into the conditioned media was significantly decreased by metformin (5 and 10 mM; P<0.05). In addition, metformin decreased levels of LPS-induced nuclear factor-κB phosphorylation. These data suggest that metformin may provide beneficial anti-inflammatory effects on CSMCs and it may be utilized as an adjunct therapy for patients suffering from IBD.

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The Epithelial Danger Signal IL-1α Is a Potent Activator of Fibroblasts and Reactivator of Intestinal Inflammation

Cited by 66 publications

References 63 publications

Oral administration of a recombinant cholera toxin B subunit promotes mucosal healing in the colon

Oral administration of a recombinant cholera toxin B subunit promotes mucosal healing in the colon

IL-1 in Colon Inflammation, Colon Carcinogenesis and Invasiveness of Colon Cancer

Metformin exerts anti‑inflammatory effects on mouse colon smooth muscle cells in�vitro

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