Anti-Tumor Necrosis Factor Therapy in Inflammatory Bowel Disease

G. Rogler, H. Herfarth, T. Hibi, O. H. Nielsen

• Editorial: S. Karger
• Año: 2015
• ISBN:
  9783318054743
• Categoría: Medicine
• Categoría: Rheumatology, Orthopedics & Prosthetics

The introduction of anti-tumour necrosis factor (TNF) antibodies into the treatment of patients with IBD about fifteen years ago has dramatically improved the quality of life for patients with severe Crohn's disease and ulcerative colitis. But despite the fact this therapeutic approach has been around for quite some time, there has been no comprehensive overview to date. The book at hand aims to amend this shortcoming, presenting for the first time a thorough overview on TNF action, mechanisms of anti-TNF therapy, treatment strategies, side effects, monitoring, biosimilars and related issues. Including state-of-the-art information and research results, this publication will be a valuable source of information and guide clinicians to the optimal treatment decision, improving the quality of life of patients with inflammatory bowel disease. Moreover, rheumatologists or even dermatologists might also find this book of interest.

Physiological Role of TNF in Mucosal Immunology

Rogler G, Herfarth H, Hibi T, Nielsen OH (eds): Anti-Tumor Necrosis Factor Therapy in Inflammatory Bowel Disease.
Front Gastrointest Res. Basel, Karger, 2015, vol 34, pp 1-8 (DOI: 10.1159/000381380)

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The Effect of TNF-α on the Regulation of Epithelial Function in Inflammatory Bowel Disease

Kiichiro Tsuchiya

Department of Advanced Therapeutics for Gastrointestinal Diseases, Graduate School of Tokyo Medical and Dental University, Tokyo, Japan

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Abstract

TNF-α is a crucial cytokine in inflammatory bowel disease (IBD) because anti-TNF-α therapy very effectively mitigates the disease. Inhibiting TNF-α induces not only the suppression of inflammation but also mucosal healing, suggesting that TNF-α may be involved in the mucosal damage observed in IBD. Although it has not been completely elucidated how TNF-α damages intestinal epithelial cells (IECs), recent reports have shown various effects of TNF-α on IECs that may be involved in the pathogenesis of IBD. In this section, we review the various functions of TNF-α in IECs, such as barrier function, cell survival, differentiation, and carcinogenesis, in IBD.

© 2015 S. Karger AG, Basel

Introduction

The gut epithelium undergoes continual renewal throughout adult life to maintain the proper architecture and function of intestinal crypts [1]. The epithelial layer is a highly dynamic tissue with high epithelial cell turnover, which is effectuated by cell shedding at the villus tip, the constant proliferation of stem cells, and the transient amplification of cells along the crypt-villus axis. This process involves highly coordinated regulation of the induction of cellular differentiation, and the cessation of proliferation is affected by various intracellular signaling pathways such as Notch, Wnt, and bone morphogenetic protein [2, 3]. Recent studies have shown that dysregulation of the differentiation system for prompt intestinal epithelial cell (IEC) formation induces the pathology of inflammatory bowel disease (IBD) [4, 5] because a central function of IECs is to control the mucosal barrier, which is essential for maintaining the luminal environment [6]. In particular, aberrant Notch signaling induced by inflammation in patients with ulcerative colitis (UC) leads to the lack of IEC differentiation, resulting in goblet cell depletion [4]. Goblet cells play a role in the mucosal barrier by secreting glycoprotein-rich mucus into the intestinal lumen, suggesting that inflammation may damage the mucosal barrier [7]. In addition, Paneth cells at the base of crypts in the small intestine secrete antimicrobial agents that prevent the gut microbiota from invading the body [8, 9]. The number of Paneth cells is also reduced in ileal lesions of patients with Crohn's disease (CD) [10]. Moreover, the recognition of bacteria by Paneth cells is weakened because of the genetic mutation of NOD2 or autophagy-related genes [11], indicating that the barrier function is impaired by both inflammation and genetic factors. Taken together, inflammation of the intestine in IBD patients may directly cause the dysfunction of IECs, although the precise mechanism remains unknown. TNF-α is an important proinflammatory cytokine that plays a central role in intestinal inflammation [12] because elevated serum levels of TNF-α in IBD patients have previously been reported [13]. Moreover, single nucleotide polymorphisms identified in genome-wide association studies indicated genes such as RELA, NFKB1, TNFSF15 [14], and TNFAIP3/A20 [15] as potential risk alleles; these results link alterations in TNF-α signaling to IBD. Antibodies targeting TNF-α have been the most successful approach in the clinical management of IBD, highlighting the importance and the clinical relevance of TNF-α function to not only intestinal inflammation but also mucosal healing [16-18]. In this section, we review TNF-α as a controller of multiple cellular processes, such as inflammatory mediator production, cell proliferation, cell survival, carcinogenesis, and different cell death modalities, that are intricately linked to the epithelial response to injury.

TNF-α Signaling Pathways in Intestinal Epithelial Cells

TNF-α is produced by immune cells and stromal cells invading the inflamed mucosa and by the intestinal epithelium stimulated via Toll-like receptors. The transmembrane protein pro-TNF-α is cleaved by a disintegrin and metallopeptidase domain 17 [19], releasing a biologically active trimeric form [20]. Both receptors for TNF-α, TNFRSF1A (TNF-R1) and TNFRSF1B (TNF-R2), are expressed in IECs and transmit the intracellular signaling of TNF-α [21-23]. The cytoplasmic domains of TNF-R1 and TNF-R2 are known to be associated with TNF receptor-associated factor 2, which induces the activation of IKK. Activated IKK subsequently induces the phosphorylation of IκB, resulting in the activation of NF-κB, which consists of p50 and RelA/p65, because of the dissociation of the IκB/NF-κB complex. TNF-R1 signaling leads to a variety of intracellular events, eventually activating two major transcription factors, NF-κB and c-Jun. Ligand-activated TNF-R1 is recognized by the adaptor protein TNF receptor-associated death domain (TRADD), which recruits additional adaptor proteins such as receptor-interacting serine/threonine kinase 1 (RIPK1) [24] and TNF receptor-associated factor 2 [25] to form a membrane-bound complex. Furthermore, TRADD interacts with the adaptor protein Fasassociated death domain (FADD) via death domains, leading to the recruitment of caspase-8 to a cytoplasmic complex. Caspase-8 plays a central role in the regulation of cell death pathways such as apoptosis and necroptosis [26]. However, TNFR2, which is not coupled with the FADD/TRADD complex, does not induce proapoptotic signaling upon interaction with TNF-α. TNF-R2 has been shown to mediate the upregulation of myosin light chain kinase (MLCK), which increases paracellular permeability via the regulation of tight junctions (TJs) [27-29].

The Regulation of Intestinal Epithelial Cell Differentiation by TNF-α

IECs consist of five types of cells: goblet cells, entero-endocrine cells, Paneth cells, Tuft cells, and enterocytes [30]. These secretory cells play a role in the mucosal barrier by secreting a variety of peptides depending on the cell type [31]. The dysregulation of IEC has been reported in IBD; for instance, aberrant Notch signaling may induce the proliferation of IECs to maintain the mucosa, although the differentiation of IECs is suppressed, as shown by goblet cell depletion [32, 33]. In a dextran sulfate sodium (DSS) colitis model, treatment with a Notch signaling inhibitor, which induces goblet cell differentiation, worsens the mucosal damage and consequently suppresses cell proliferation [4], suggesting that Notch signaling may not serve as a target for mucosal healing in UC. Another report indicated that caudal type homeobox 2 (CDX2) expression is reduced in the mucosa in UC [34], indicating that the dysregulation of the molecular mechanisms underlying intestinal differentiation may be critical for the pathogenesis of UC. CDX2 is an intestine-specific transcription factor that is essential for the regulation of genes related to epithelial functions. CDX2 is a crucial regulator of intestinal epithelial function, including the control of the balance between IEC differentiation and proliferation [35]. We have previously reported that CDX2 directly induces Atonal homolog 1 (Atoh1) expression by binding to the 3’ region of the Atoh1 gene but that HES1 directly suppresses Atoh1 expression by binding to the 5’ promoter region of the Atoh1 gene [33]. Moreover, we have shown that CDX2 can induce Atoh1 expression despite HES1 expression via Notch signaling activation, suggesting that CDX2 may promote both the proliferation and the differentiation of IECs. Therefore, the reduced CDX2 expression level in the mucosa in IBD indicates that the dys-regulation of the molecular mechanism underlying intestinal differentiation may be critical for the pathogenesis of IBD. A previous report has shown that TNF-α suppresses the expression of CDX2 in a colonic cell line [36], suggesting that the overexpression of TNF-α in IECs may induce goblet cell depletion in IBD. In a mouse model, intestine-specific TNF-α overexpression induced Crohn's-like ileitis [20, 37], supporting the concept that the local TNF-α microenvironment in IECs is the determining factor for the development of an inflammatory phenotype.

TNF-α in Tight Junction Modulation

TJs between adjacent IECs regulate the semi-permeable barrier in the intestine [38]. The selectivity of TJs controls the trafficking of luminal antigens through the mucosa and facilitates the interaction between the bacterial flora and the mucosal immune system [38]. TNF-α regulates intestinal permeability by mediating TJ remodeling following the activation of MLCK. The phosphorylation of the regulatory light-chain of myosin II by MLCK induces actomyosin ring contraction. The redistribution of peri-junctional actin, ZO-1, claudin, and occludin from the TJ complex subsequently causes an increase in paracellular flux [39, 40]. Mice expressing constitutively active MLCK display increased barrier permeability and inflammatory cytokine production. Moreover, patients with CD have increased intestinal expression and activity of MLCK [41], implicating a TNF-mediated pathway in the reduced barrier function that is a feature of IBD. Therefore, factors that control TNF-induced changes in IEC TJs may play critical roles in barrier function and in the prevention of IBD. Kolodziej et al. demonstrated that TNFAIP3, also known ...