Genome-wide association studies have identified several inflammatory bowel disease (IBD) susceptibility loci that contain genes that encode cytokines and proteins involved in cytokine signalling. In particular, recent work has found that loss-of-function mutations in the genes encoding interleukin-10 (IL-10) and the IL-10 receptor are associated with very early-onset IBD.
Cytokines not only drive intestinal inflammation and diarrhoea in IBD but may also regulate extra-intestinal disease manifestations (for example, arthralgia or arthritis) and systemic effects. Furthermore, cytokines seem to have a crucial role in driving complications of IBD such as intestinal stenosis, fistula formation and colitis-associated neoplasias.
Studies using tissue from patients with IBD and animal models of IBD have identified cytokines as potential new targets for the therapy of intestinal inflammation. Relevant targets include pro-inflammatory cytokines, such as IL-6, IL-12, IL-23 and IL-21, as well as anti-inflammatory cytokines, such as IL-10 and transforming growth factor-β.
Anti-cytokine therapies involving tumour necrosis factor (TNF)-specific agents form an important cornerstone of clinical therapy in both Crohn's disease and ulcerative colitis. TNF-specific antibodies suppress chronic intestinal inflammation and may induce mucosal healing in IBD.
Several new anti-cytokine agents have shown little or no efficacy in IBD, suggesting the existence of a highly regulated cytokine network. New approaches for anti-cytokine therapies may include multi-cytokine blockers, such as tofacitinib.
New cytokine targets, optimized delivery systems for anti-cytokine agents and personalized medicine may pave the way towards more effective clinical approaches by targeting the expression or function of pro-inflammatory and anti-inflammatory cytokines in patients with IBD.
Cytokines have a crucial role in the pathogenesis of inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, where they control multiple aspects of the inflammatory response. In particular, the imbalance between pro-inflammatory and anti-inflammatory cytokines that occurs in IBD impedes the resolution of inflammation and instead leads to disease perpetuation and tissue destruction. Recent studies suggest the existence of a network of regulatory cytokines that has important implications for disease progression. In this Review, we discuss the role of cytokines produced by innate and adaptive immune cells, as well as their relevance to the future therapy of IBD.
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The research of M.F.N. is supported by the Clinical Research Group (CEDER) of the German Research Council (DFG), the DFG Collaborative Research Centers 643 and 796, The German Cancer Aid organization, the United European Gastroenterology Research Prize, the DFG Graduate School of Excellence School in Advanced Optical Technologies, the Excellence program of the Friedrich-Alexander-Universität Erlangen-Nürnberg (Ludwig Demling Center), Germany, and the Interdisciplinary Center for Clinical Research (IZKF) and ELAN (Fonds für Forschung und Lehre) programmes of the University Erlangen-Nürnberg, Germany.
M.F.N. has served as an adviser for MSD Pharmaceuticals, AbbVie, Pentax Corporation and Giuliani Pharma.
- Innate lymphoid cells
(ILCs). Cells that develop from a common lymphoid progenitor but that do not express lineage markers associated with other lymphocytes. These cells rapidly secrete effector cytokines in response to activation and have been subdivided into three main groups on the basis of whether they produce T helper 1 (TH1)-, TH2- or TH17-type cytokines.
- Acute-phase proteins
A group of proteins — including C-reactive protein, serum amyloid A and fibrinogen — secreted by hepatocytes into the blood in increased or decreased quantities in response to trauma, inflammation or disease. These proteins can be inhibitors or mediators of inflammatory processes.
A condition of severe weight loss, muscle wasting and debility that is caused by prolonged disease and is thought to be mediated by neuroimmunoendocrine interactions.
A programmed form of necrotic cell death that is regulated by receptor-interacting protein kinase 1 (RIPK1) and RIPK3.
Therapeutics that are based on the heavy-chain antibodies found in camels and llamas. Similarly to conventional antibodies, they have heavy-chain variable and constant regions but they lack light-chain domains.
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Neurath, M. Cytokines in inflammatory bowel disease. Nat Rev Immunol 14, 329–342 (2014). https://doi.org/10.1038/nri3661
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