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Review
. 2023 May 14;29(18):2733-2746.
doi: 10.3748/wjg.v29.i18.2733.

Study of tumor necrosis factor receptor in the inflammatory bowel disease

Roberta Figueiroa Souza  1 , Marcos Antônio Ferreira Caetano  1 , Henrique Inhauser Riceti Magalhães  2 , Patricia Castelucci  3
Affiliations
Review

Study of tumor necrosis factor receptor in the inflammatory bowel disease

Roberta Figueiroa Souza et al. World J Gastroenterol. .

Abstract

Ulcerative colitis (UC) and Crohn's disease (CD) are part of Inflammatory Bowel Diseases (IBD) and have pathophysiological processes such as bowel necrosis and enteric neurons and enteric glial cells. In addition, the main inflammatory mediator is related to the tumor necrosis factor-alpha (TNF-α). TNF-α is a me-diator of the intestinal inflammatory processes, thus being one of the main cytokines involved in the pathogenesis of IBD, however, its levels, when measured, are present in the serum of patients with IBD. In addition, TNF-α plays an important role in promoting inflammation, such as the production of interleukins (IL), for instance IL-1β and IL-6. There are two receptors for TNF as following: The tumor necrosis factor 1 receptor (TNFR1); and the tumor necrosis factor 2 receptor (TNFR2). They are involved in the pathogenesis of IBD and their receptors have been detected in IBD and their expression is correlated with disease activity. The soluble TNF form binds to the TNFR1 receptor with, and its activation results in a signaling cascade effects such as apoptosis, cell proliferation and cytokine secretion. In contrast, the transmembrane TNF form can bind both to TNFR1 and TNFR2. Recent studies have suggested that TNF-α is one of the main pro-inflammatory cytokines involved in the pathogenesis of IBD, since TNF levels are present in the serum of both patients with UC and CD. Intravenous and subcutaneous biologics targeting TNF-α have revolutionized the treatment of IBD, thus becoming the best available agents to induce and maintain IBD remission. The application of antibodies aimed at neutralizing TNF-α in patients with IBD that induce a satisfactory clinical response in up to 60% of patients, and also induced long-term maintenance of disease remission in most patients. It has been suggested that anti-TNF-α agents inactivate the pro-inflammatory cytokine TNF-α by direct neutralization, i.e., resulting in suppression of inflammation. However, anti-TNF-α antibodies perform more complex functions than a simple blockade.

Keywords: Enteric nervous system; Inflammatory bowel diseases; Tumor necrosis factor 1 receptor; Tumor necrosis factor 2 receptor; tumor necrosis factor-alpha.

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Conflict of interest statement

Conflict-of-interest statement: Authors declare no conflict of interests for this article.

Figures

Figure 1
Figure 1
Tumor necrosis factor-alpha signaling pathways. TNF-α: Tumor necrosis factor-alpha; TNFR1: Tumor necrosis factor receptor 1; TNFR2: Tumor necrosis factor receptor 2; TRADD: TNF receptor associated protein with death domain; FADD: FAS-associated death domain protein; cIAPS: Cellular inhibitor of apoptosis; MEKK: MAPK kinase kinas; JNK: N-terminal jun kinase; ASK1: Apoptosis signal-regulating kinase 1; IKK: IκB kinase; NF-κB: Nuclear factor κB; RIP: Receptor-interacting protein kinase. Created with BioRender.com.
Figure 2
Figure 2
Biological medicines for inflammatory bowel diseases. Biological medicines used for the treatment of inflammatory bowel diseases (IBD) can be classified into anti- Tumor necrosis factor (TNF)-α, anti-integrin and anti-interleukin therapies. Anti-TNF-α binds to TNF-α and inhibits TNF receptor activation. Infliximab, adalimumab, certolizumab pegol and golimumab are examples of anti-TNF-α used in the treatment of IBD. Vedolizumab and natalizumab are anti-integrin agents, which bind to the α4β7 integrin and prevent the migration of inflammatory cells into the intestinal tissue. Ustekinumab is an anti-interleukin that blocks interleukin (IL)-12 and IL-23, which cannot bind to IL-12 receptor and IL-23 receptor on T and B lymphocytes, thus reducing the inflammatory response in the gut. CDindication only for Crohn’s Disease; UCindication only for Ulcerative Colitis; CD/UCindication both for Crohn’s Disease and Ulcerative Colitis. TNF-α: Tumor necrosis factor-alpha; IL: Interleukin. Created with BioRender.com.
Figure 3
Figure 3
Comparison of the intestine in normal conditions and in the bowel with inflammatory bowel disease. Under normal conditions (left), the intestinal microbiota establishes a symbiotic condition with the host, the intestinal barrier is intact and functional, and there is a balance between the levels of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-12 and IL-23 and anti-inflammatory cytokines such as transforming growth factor beta and IL-10 by innate immune cells. In this way, there is a regulation of the immune response through a balance between regulatory T cells and effector T cells. Submucosal plexus (SMP) and myenteric plexus neurons are functional and controlling, respectively, fluid secretion and intestinal motility. In inflammatory bowel diseases (IBD) (right), there is an imbalance in the intestinal microbiota, the intestinal barrier is compromised, with a reduction in the mucous layer, increased epithelial permeability and consequent passage of microorganisms to the lamina propria. Innate immune cells increase the secretion of pro-inflammatory cytokines such as TNF-α, IL-12 and IL-23, which leads to a dysregulation of the immune system mediated by T cells, increasing the activity of effector T cells which, in turn, recruit cells for the inflammatory response. In IBD, submucosal edema is observed, as well as a reduction in the number of neurons in the SMP, causing changes in secretion patterns and loss of neurons in the myenteric plexus, resulting in changes in motility patterns. TNF-α: Tumor necrosis factor-alpha; IL: Interleukin. Created with BioRender.com.
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References

    1. Loddo I, Romano C. Inflammatory Bowel Disease: Genetics, Epigenetics, and Pathogenesis. Front Immunol . 2015;6:551. - PMC - PubMed
    1. Shapiro JM, Subedi S, LeLeiko NS. Inflammatory Bowel Disease. Pediatr Rev . 2016;37:337–347. - PubMed
    1. Shivashankar R, Lichtenstein GR. Mimics of Inflammatory Bowel Disease. Inflamm Bowel Dis . 2018;24:2315–2321. - PubMed
    1. Liu Y, Zhao J, Zhao Y, Zong S, Tian Y, Chen S, Li M, Liu H, Zhang Q, Jing X, Sun B, Wang H, Sun T, Yang C. Therapeutic effects of lentinan on inflammatory bowel disease and colitis-associated cancer. J Cell Mol Med . 2019;23:750–760. - PMC - PubMed
    1. Ahmad T, Satsangi J, McGovern D, Bunce M, Jewell DP. Review article: The genetics of inflammatory bowel disease. Aliment Pharmacol Ther . 2001;15:731–748. - PubMed

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