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Adalimumab prevents barrier dysfunction and antagonizes distinct effects of TNF-α on tight junction proteins and signaling pathways in intestinal epithelial cells.
Am J Physiol Gastrointest Liver Physiol. 2013 Jun 01; 304(11):G970-9.AJ

Abstract

Intestinal barrier dysfunction is pivotal in the etiology of inflammatory bowel diseases. Combined clinical and endoscopic remission ("mucosal healing") in patients who received anti-TNF-α therapies suggests restitution of the intestinal barrier, but the mechanisms involved are largely unknown. We therefore investigated the impact of the anti-TNF-α antibody adalimumab on barrier function in two in vitro models. Combined stimulation of Caco-2 and T-84 cells with interferon-γ and TNF-α resulted in a significant decrease of transepithelial electrical resistance (TEER) within 6 h that was prevented by adalimumab in concentrations down to 100 ng/ml. Adalimumab furthermore antagonized the appearance of irregular membrane undulations and prevented internalization of tight junction proteins upon cytokine exposure. In addition, TNF-α induced a downregulation of claudin-1, claudin-2, claudin-4, and occludin as well as activation of phosphatidylinositol 3-kinase signaling in T-84 but not Caco-2 cells, which was reversed by adalimumab. At the signaling level, adalimumab prevented increased phosphorylation of myosin light chain as well as activation of p38 MAPK and NF-κB accompanying the decline in TEER in both model systems. Pharmacological inhibition of NF-κB signaling partially prevented the TNF-α-induced TEER loss, whereas inhibition of p38 worsened barrier dysfunction in Caco-2 but not T-84 cells. Taken together, these data demonstrate that adalimumab prevents barrier dysfunction induced by TNF-α both functionally and structurally as well as at the level of signal transduction. Barrier protection might therefore constitute a novel mechanism how anti-TNF-α therapy contributes to epithelial restitution and tissue repair in inflammatory bowel diseases.

Authors+Show Affiliations

Department of Medicine, Division of Gastroenterology and Hepatology, Humboldt-University of Berlin, Berlin, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23538493

Citation

Fischer, Andreas, et al. "Adalimumab Prevents Barrier Dysfunction and Antagonizes Distinct Effects of TNF-α On Tight Junction Proteins and Signaling Pathways in Intestinal Epithelial Cells." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 304, no. 11, 2013, pp. G970-9.
Fischer A, Gluth M, Pape UF, et al. Adalimumab prevents barrier dysfunction and antagonizes distinct effects of TNF-α on tight junction proteins and signaling pathways in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2013;304(11):G970-9.
Fischer, A., Gluth, M., Pape, U. F., Wiedenmann, B., Theuring, F., & Baumgart, D. C. (2013). Adalimumab prevents barrier dysfunction and antagonizes distinct effects of TNF-α on tight junction proteins and signaling pathways in intestinal epithelial cells. American Journal of Physiology. Gastrointestinal and Liver Physiology, 304(11), G970-9. https://doi.org/10.1152/ajpgi.00183.2012
Fischer A, et al. Adalimumab Prevents Barrier Dysfunction and Antagonizes Distinct Effects of TNF-α On Tight Junction Proteins and Signaling Pathways in Intestinal Epithelial Cells. Am J Physiol Gastrointest Liver Physiol. 2013 Jun 1;304(11):G970-9. PubMed PMID: 23538493.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Adalimumab prevents barrier dysfunction and antagonizes distinct effects of TNF-α on tight junction proteins and signaling pathways in intestinal epithelial cells. AU - Fischer,Andreas, AU - Gluth,Markus, AU - Pape,Ulrich-Frank, AU - Wiedenmann,Bertram, AU - Theuring,Franz, AU - Baumgart,Daniel C, Y1 - 2013/03/28/ PY - 2013/3/30/entrez PY - 2013/3/30/pubmed PY - 2013/8/10/medline KW - Crohn's disease KW - IBD KW - claudin KW - intestinal barrier KW - tumor necrosis factor-α KW - ulcerative colitis SP - G970 EP - 9 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am J Physiol Gastrointest Liver Physiol VL - 304 IS - 11 N2 - Intestinal barrier dysfunction is pivotal in the etiology of inflammatory bowel diseases. Combined clinical and endoscopic remission ("mucosal healing") in patients who received anti-TNF-α therapies suggests restitution of the intestinal barrier, but the mechanisms involved are largely unknown. We therefore investigated the impact of the anti-TNF-α antibody adalimumab on barrier function in two in vitro models. Combined stimulation of Caco-2 and T-84 cells with interferon-γ and TNF-α resulted in a significant decrease of transepithelial electrical resistance (TEER) within 6 h that was prevented by adalimumab in concentrations down to 100 ng/ml. Adalimumab furthermore antagonized the appearance of irregular membrane undulations and prevented internalization of tight junction proteins upon cytokine exposure. In addition, TNF-α induced a downregulation of claudin-1, claudin-2, claudin-4, and occludin as well as activation of phosphatidylinositol 3-kinase signaling in T-84 but not Caco-2 cells, which was reversed by adalimumab. At the signaling level, adalimumab prevented increased phosphorylation of myosin light chain as well as activation of p38 MAPK and NF-κB accompanying the decline in TEER in both model systems. Pharmacological inhibition of NF-κB signaling partially prevented the TNF-α-induced TEER loss, whereas inhibition of p38 worsened barrier dysfunction in Caco-2 but not T-84 cells. Taken together, these data demonstrate that adalimumab prevents barrier dysfunction induced by TNF-α both functionally and structurally as well as at the level of signal transduction. Barrier protection might therefore constitute a novel mechanism how anti-TNF-α therapy contributes to epithelial restitution and tissue repair in inflammatory bowel diseases. SN - 1522-1547 UR - https://www.unboundmedicine.com/medline/citation/23538493/Adalimumab_prevents_barrier_dysfunction_and_antagonizes_distinct_effects_of_TNF_α_on_tight_junction_proteins_and_signaling_pathways_in_intestinal_epithelial_cells_ L2 - https://journals.physiology.org/doi/10.1152/ajpgi.00183.2012?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -