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Increase in Epithelial Permeability and Cell Metabolism by High Mobility Group Box 1, Inflammatory Cytokines and TPEN in Caco-2 Cells as a Novel Model of Inflammatory Bowel Disease.

ABSTRACT: High mobility group box 1 protein (HMGB1) is involved in the pathogenesis of inflammatory bowel disease (IBD). Patients with IBD develop zinc deficiency. However, the detailed roles of HMGB1 and zinc deficiency in the intestinal epithelial barrier and cellular metabolism of IBD remain unknown. In the present study, Caco-2 cells in 2D culture and 2.5D Matrigel culture were pretreated with transforming growth factor-? (TGF-?) type 1 receptor kinase inhibitor EW-7197, epidermal growth factor receptor (EGFR) kinase inhibitor AG-1478 and a TNF? antibody before treatment with HMGB1 and inflammatory cytokines (TNF? and IFN?). EW-7197, AG-1478 and the TNF? antibody prevented hyperpermeability induced by HMGB1 and inflammatory cytokines in 2.5D culture. HMGB1 affected cilia formation in 2.5D culture. EW-7197, AG-1478 and the TNF? antibody prevented the increase in cell metabolism induced by HMGB1 and inflammatory cytokines in 2D culture. Furthermore, ZnSO₄ prevented the hyperpermeability induced by zinc chelator TPEN in 2.5D culture. ZnSO₄ and TPEN induced cellular metabolism in 2D culture. The disruption of the epithelial barrier induced by HMGB1 and inflammatory cytokines contributed to TGF-?/EGF signaling in Caco-2 cells. The TNF? antibody and ZnSO₄ as well as EW-7197 and AG-1478 may have potential for use in therapy for IBD.

SUBMITTER: Miyakawa M

PROVIDER: S-EPMC7696423 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Increase in Epithelial Permeability and Cell Metabolism by High Mobility Group Box 1, Inflammatory Cytokines and TPEN in Caco-2 Cells as a Novel Model of Inflammatory Bowel Disease.

Miyakawa Maki M Konno Takumi T Kohno Takayuki T Kikuchi Shin S Tanaka Hiroki H Kojima Takashi T

International journal of molecular sciences 20201110 22

High mobility group box 1 protein (HMGB1) is involved in the pathogenesis of inflammatory bowel disease (IBD). Patients with IBD develop zinc deficiency. However, the detailed roles of HMGB1 and zinc deficiency in the intestinal epithelial barrier and cellular metabolism of IBD remain unknown. In the present study, Caco-2 cells in 2D culture and 2.5D Matrigel culture were pretreated with transforming growth factor-β (TGF-β) type 1 receptor kinase inhibitor EW-7197, epidermal growth factor recept ...[more]

PMID: 33182652

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Project description:Trauma is common in dogs and causes significant morbidity and mortality, but it remains challenging to predict the prognosis of dogs with traumatic injuries. This study aimed to quantify plasma high-mobility group box-1 (HMGB-1) and cytokine concentrations in dogs with moderate-to-severe trauma, and to evaluate the association between these biomarkers and the injury severity and survival to discharge. Using a prospective, observational case-control study design, 49 dogs with an animal trauma triage (ATT) score ≥3 were consecutively enrolled from 07/2015 to 10/2017 and followed to hospital discharge. Dogs <3 kg and those with pre-existing coagulopathies were excluded. Thirty three healthy control dogs were also enrolled. Illness and injury severity scores including the acute patient physiologic and laboratory evaluation (APPLE) were calculated using at-presentation data. Plasma HMGB-1 concentrations were measured by ELISA; concentrations of 13 cytokines were measured using multiplex bead-based assays and separately concentrations of 4 cytokines were measured using a multiplex canine-specific ELISA. All biomarkers were measured in duplicate. Mann-Whitney U tests were used to compare biomarker concentrations between groups and between survivors and non-survivors. Associations between biomarkers were evaluated using Spearman's correlation coefficients. Independent predictors of survival were identified using multivariable logistic regression. Alpha was set at 0.05. Plasma concentrations of HMGB-1, interleukin-6, C-X-C motif chemokine-8, keratinocyte chemoattractant-like, and C-C chemokine ligand-2 were significantly greater in injured dogs vs. controls (all P ≤ 0.011). In univariate analyses, HMGB-1 was significantly greater in non-survivors 46.67 ng/mL (8.94-84.73) compared to survivors 6.03 ng/mL (3.30-15.75), (P = 0.003). Neither HMGB-1 or the cytokines were associated with survival independent of illness severity as measured by the APPLE score, however.

Project description:IntroductionHigh mobility group box 1 (HMGB1) is released by necrotic cells or secreted in response to inflammatory stimuli. Extracellular HMGB1 may act as a pro-inflammatory cytokine in rheumatoid arthritis. We have recently reported that HMGB1 is released by osteoarthritic synoviocytes after activation with interleukin-1beta (IL-1?) The present study investigated the role of HMGB1 in synovial inflammation in osteoarthritis (OA).MethodsHMGB1 was determined in human synovium using immunohistochemistry, comparing normal to OA. OA synoviocytes were incubated with HMGB1 at 15 or 25 ng/ml in the absence or presence of IL-1? (10 ng/ml). Gene expression was analyzed by quantitative PCR and protein expression by Western Blot and ELISA. Matrix metalloproteinase (MMP) activity was studied by fluorometric procedures and nuclear factor (NF)-?B activation by transient transfection with a NF-?B-luciferase plasmid.ResultsIn the normal synovium, HMGB1 was found in the synovial lining cells, sublining cells, and in the vascular wall cells. The distribution of HMGB1 in OA synovium was similar but the number of HMGB1 positive cells was higher and HMGB1 was also present in infiltrated cells. In normal synovial membrane cells, HMGB1 was found mostly in the nuclei, whereas in OA, HMGB1 was generally found mostly in the cytoplasm. In OA synoviocytes, HMGB1 alone at concentrations of 15 or 25 ng/ml did not affect the production of IL-6, IL-8, CCL2, CCL20, MMP-1 or MMP-3, but in the presence of IL-1?, a significant potentiation of protein and mRNA expression, as well as MMP activity was observed. HMGB1 also enhanced the phosphorylated ERK1/2 and p38 levels, with a lower effect on phosphorylated Akt. In contrast, JNK1/2 phosphorylation was not affected. In addition, HMGB1 at 25 ng/ml significantly potentiated NF-?B activation in the presence of IL-1?.ConclusionsOur results indicate that HMGB1 is overexpressed in OA synovium and mostly present in extracellular form. In OA synoviocytes, HMGB1 cooperates with IL-1? to amplify the inflammatory response leading to the production of a number of cytokines, chemokines and MMPs. Our data support a pro-inflammatory role for this protein contributing to synovitis and articular destruction in OA.

Dataset Information

Increase in Epithelial Permeability and Cell Metabolism by High Mobility Group Box 1, Inflammatory Cytokines and TPEN in Caco-2 Cells as a Novel Model of Inflammatory Bowel Disease.

Publications

Increase in Epithelial Permeability and Cell Metabolism by High Mobility Group Box 1, Inflammatory Cytokines and TPEN in Caco-2 Cells as a Novel Model of Inflammatory Bowel Disease.

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