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-β (TGF-β) type 1 receptor kinase inhibitor EW-7197, epidermal growth factor receptor (EGFR) kinase inhibitor AG-1478 and a TNFα antibody before treatment with HMGB1 and inflammatory cytokines (TNFα and IFNγ). EW-7197, AG-1478 and the TNFα 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 TNFα 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-β/EGF signaling in Caco-2 cells. The TNFα antibody and ZnSO4 as well as EW-7197 and AG-1478 may have potential for use in therapy for IBD.

• Authors: Maki Miyakawa, Takumi Konno, Takayuki Kohno, Shin Kikuchi, Hiroki Tanaka, Takashi Kojima
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 22 (Nov 10 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33182652 (Publication Type: Journal Article)

Chemical References

• Aniline Compounds
• Chelating Agents
• Cytokines
• Ethylenediamines
• HMGB1 Protein
• HMGB1 protein, human
• IFNG protein, human
• Inflammation Mediators
• LSR protein, human
• Quinazolines
• Receptors, Lipoprotein
• TNF protein, human
• Transcription Factors
• Triazoles
• Tumor Necrosis Factor-alpha
• Tyrphostins
• RTKI cpd
• vactosertib
• Zinc Sulfate
• Interferon-gamma
• N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine

Topics

• Aniline Compounds (pharmacology)
• Caco-2 Cells
• Chelating Agents (pharmacology)
• Cytokines (metabolism)
• Ethylenediamines (pharmacology)
• HMGB1 Protein (metabolism, pharmacology)
• Humans
• Inflammation Mediators (metabolism)
• Inflammatory Bowel Diseases (drug therapy, metabolism, pathology)
• Interferon-gamma (metabolism, pharmacology)
• Intestinal Mucosa (drug effects, metabolism, pathology)
• Models, Biological
• Permeability (drug effects)
• Quinazolines (pharmacology)
• Receptors, Lipoprotein (metabolism)
• Signal Transduction
• Transcription Factors (metabolism)
• Triazoles (pharmacology)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, pharmacology)
• Tyrphostins (pharmacology)
• Zinc Sulfate (pharmacology)