Abstract
The intestinal epithelium constitutes an indispensable single-layered barrier to protect the body from invading pathogens, antigens or toxins. At the same time, beneficial nutrients and water have to be absorbed by the epithelium. To prevent development of intestinal inflammation or tumour formation, intestinal homeostasis has to be tightly controlled and therefore a strict balance between cell death and proliferation has to be maintained. The proinflammatory cytokine tumour necrosis factor alpha (TNFα) was shown to play a striking role for the regulation of this balance in the gut. Depending on the cellular conditions, on the one hand TNFα is able to mediate cell survival by activating NFκB signalling. On the other hand, TNFα might trigger cell death, in particular caspase-dependent apoptosis but also caspase-independent programmed necrosis. By regulating these cell death and survival mechanisms, TNFα exerts a variety of beneficial functions in the intestine. However, TNFα signalling is also supposed to play a critical role for the pathogenesis of inflammatory bowel disease (IBD), infectious diseases, intestinal wound healing and tumour formation. Here we review the literature about the physiological and pathophysiological role of TNFα signalling for the maintenance of intestinal homeostasis and the benefits and difficulties of anti-TNFα treatment during IBD.
Highlights
The Tumour Necrosis Factor (TNF) Superfamily is composed of 19 ligands and 29 receptors [1,2]
That LPS-TLR4-signaling induced TNFα production in intestinal immune cells, further acting on epithelial cells via TNFR1, whereas dsRNA-TLR3 signalling rather directly mediated cell death in epithelial cells (Figure 5)
Crohn’s disease (CD) and ulcerative colitis (UC) represent the major entities of inflammatory bowel disease (IBD), which are defined as relapsing disorders of the gastrointestinal tract that are pathologically characterized by mucosal inflammation and epithelial damage not due to identifiable pathogens [156]
Summary
The Tumour Necrosis Factor (TNF) Superfamily is composed of 19 ligands and 29 receptors [1,2]. The tumour necrosis factor receptors (TNFR) belonging to this family, share cysteine-rich extracellular domains, which bind to the TNF homology domains of the TNF ligands [3]. TNF- and TNFR-mediated signalling pathways are involved in the regulation of cell survival, proliferation, morphogenetic changes and cell death [2]. Members of the Tumour Necrosis Factor Superfamily are expressed by many different cell types in the human body, for example, immune cells, hematopoietic cells, epithelial and endothelial cells under physiologic and under pathologic conditions [2,4]. In the 1980s, two different types of TNF proteins were identified, which were called TNFα and TNFβ. The TNFα protein is produced by many different cell types in the human body, the main producers are the cells from the monocytic lineage, for example, macrophages [11]. Activation of the two TNFRs can mediate cell survival via activation of the classical and alternative NFκB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) as well as MAP Kinase pathways [25]
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