Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 14, 2016; 22(42): 9300-9313
Published online Nov 14, 2016. doi: 10.3748/wjg.v22.i42.9300
Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases
Ulrike Billmeier, Walburga Dieterich, Markus F Neurath, Raja Atreya
Ulrike Billmeier, Walburga Dieterich, Markus F Neurath, Raja Atreya, Medical Clinic 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
Author contributions: Billmeier U wrote the manuscript; and Dieterich W, Neurath MF and Atreya R critically reviewed the manuscript.
Supported by DFG-CRC1181 - Project number (C02); and a research operating grant from the International Organization for the Study of Inflammatory Bowel Diseases.
Conflict-of-interest statement: Raja Atreya has served as advisor for AbbVie and Markus F Neurath has served as advisor for MSD, AbbVie, Takeda, Boehringer, Giuliani.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Raja Atreya, MD, Professor, Medical Clinic 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany.
Telephone: +49-9131-8535115 Fax: +49-9131-8535116
Received: July 10, 2016
Peer-review started: July 13, 2016
First decision: July 29, 2016
Revised: September 15, 2016
Accepted: October 10, 2016
Article in press: October 10, 2016
Published online: November 14, 2016
Processing time: 125 Days and 10.2 Hours

Anti-tumor necrosis factor (TNF) antibodies are successfully used in the therapy of inflammatory bowel diseases (IBD). However, the molecular mechanism of action of these agents is still a matter of debate. Apart from neutralization of TNF, influence on the intestinal barrier function, induction of apoptosis in mucosal immune cells, formation of regulatory macrophages as well as other immune modulating properties have been discussed as central features. Nevertheless, clinically effective anti-TNF antibodies were shown to differ in their mode-of-action in vivo and in vitro. Furthermore, the anti-TNF agent etanercept is effective in the treatment of rheumatoid arthritis but failed to induce clinical response in Crohn’s disease patients, suggesting different contributions of TNF in the pathogenesis of these inflammatory diseases. In the following, we will review different aspects regarding the mechanism of action of anti-TNF agents in general and analyze comparatively different effects of each anti-TNF agent such as TNF neutralization, modulation of the immune system, reverse signaling and induction of apoptosis. We discuss the relevance of the membrane-bound form of TNF compared to the soluble form for the immunopathogenesis of IBD. Furthermore, we review reports that could lead to personalized medicine approaches regarding treatment with anti-TNF antibodies in chronic intestinal inflammation, by predicting response to therapy.

Keywords: Mucosal immunology, Lamina propria mononuclear cells, Crohn’s disease, Ulcerative colitis, Transmembrane tumor necrosis factor, Apoptosis

Core tip: To improve the response rates of patients with inflammatory bowel diseases to anti-tumor necrosis factor (TNF) therapy, it is mandatory to understand the pleiotropic effects of these agents. Herein, we overview and discuss several immunological targets of anti-TNF antibody application and highlight the most important findings.