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Inflammatory Bowel Disease Learning Zone

Inflammatory Targets in IBD

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Inflammatory Targets in IBD

Novel inflammatory targets are already being exploited in the management of IBD while a significant number are currently under investigation. This section of the Learning Zone describes the inflammatory targets currently used in the clinic as well as those at an advanced stage of development in the search for improved ulcerative colitis and Crohn’s disease therapies.

Interleukin 12/23

The cytokines interleukin (IL)-12 and IL-23 are heterodimeric proteins containing two subunits: the p40 subunit is common to both cytokines; p35 and p19 subunits are present in IL-12 and IL-23, respectively (Coskun et al., 2017; Currò et al., 2017). 

IL-12 and IL-23 are both induced as part of the innate immune response in patients with IBD (Neurath, 2017). Indeed, these are among the main cytokines arising as a consequence of this (Argollo et al., 2017).

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Integrin and mucosal vascular addressin cell adhesion molecule

Integrins on the surface of leucocytes can bind to specific molecules on other cells to facilitate “immune cell homing” (Currò et al., 2017). In IBD, leucocytes bearing the α4β7 integrin selectively bind to the mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), which is expressed in the gut (Bravatà et al., 2015). 

The process is facilitated by MAdCAM-1 expression being upregulated by pro-inflammatory cytokines released from activated T cells that have migrated to gastrointestinal mucosa (Bravatà et al., 2015).

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Janus Family Kinase

Janus family kinases (JAKs) are a subgroup of non-receptor protein tyrosine kinases comprising four members (Ghoreschi et al., 2009; Hsu and Armstrong, 2014):

 

  • JAK1
  • JAK2
  • JAK3
  • TYK2.

These are involved in a variety of processes, including immunity, with different cytokines signalling through different JAK members to modulate immune responses in different ways (Ghoreschi et al., 2009).

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SMAD7

SMAD7 is an intracellular protein that inhibits transforming growth factor beta 1 (TGF-β1) and may be overexpressed in IBD (Argollo et al., 2017; Currò et al., 2017; Nielsen et al., 2016).

TGF-β1, a cytokine produced by mucosal cells, downregulates immune responses by acting on several types of immune cells (Nielsen et al., 2016). Inhibition of TGF-β1 is thus liable to have pro-inflammatory effects.

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Sphingosine 1-phosphate

Sphingosine 1-phosphate (S1P) is a phospholipid that can exert regulatory effects on various biological processes via binding to five transmembrane S1P receptors (S1P1–5) (Argollo et al., 2017; Currò et al., 2017; Nielsen et al., 2016). Levels of S1P are increased at inflammatory sites (Argollo et al., 2017) and S1P1 receptors are expressed on lymphocytes (Nielsen et al., 2016). 

When S1P binds to S1P1 on lymphocytes in lymph nodes, the lymphocytes are released from the lymph nodes and migrate to inflammatory sites, where they can contribute to immune-mediated pathology (Currò et al., 2017; Nielsen et al., 2016).

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Tumour Necrosis Factor Alpha

Tumour necrosis factor alpha (TNFα) is a cytokine produced by a range of cells (Monteleone et al., 2013). It has two receptor subtypes, and binding to these triggers inflammatory pathways (Monteleone et al., 2013).

In patients with IBD, levels of TNFα are increased systemically as well in the intestine (Holleran et al., 2017). TNFα is one of the main pro-inflammatory cytokines in IBD, with a key role in pathogenesis (Argollo et al., 2017; Pedersen et al., 2014; Neurath, 2014).

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Welcome:

Inflammatory Targets in IBD References

Interleukin 12/23

Argollo M, Fiorino G, Hindryckx P, Peyrin-Biroulet L, Danese S. Novel therapeutic targets for inflammatory bowel disease. J Autoimmun. 2017;85:103–16.

Coskun M, Vermeire S, Nielsen OH. Novel targeted therapies for inflammatory bowel disease. Trends Pharmacol Sci. 2017;38:127–42.

Currò D, Pugliese D, Armuzzi A. Frontiers in drug research and development for inflammatory bowel disease. Front Pharmacol. 2017;8:400.

Neurath MF. Current and emerging therapeutic targets for IBD. Nat Rev Gasyroenterol Hepatol. 2017;14:269–78.

Integrin and MAdCAM

Bravatà I, Allocca M, Fiorino G, Danese S. Integrins and adhesion molecules as targets to treat inflammatory bowel disease. Curr Opin Pharmacol. 2015;25:67–71.

Coskun M, Vermeire S, Nielsen OH. Novel targeted therapies for inflammatory bowel disease. Trends Pharmacol Sci. 2017;38:127–42.

Currò D, Pugliese D, Armuzzi A. Frontiers in drug research and development for inflammatory bowel disease. Front Pharmacol. 2017;8:400.

Entyvio Summary of Product Characteristics. 2018. Available from: https://www.medicines.org.uk/emc/medicine/28980. Last accessed Jan 2018.

Janus Family Kinase

Coskun M, Salem M, Pedersen J, Nielsen OH. Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol Res. 2013;76:1–8.

Ghoreschi K, Laurence A, O'Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009;228:273–87.

Hsu L, Armstrong AW. JAK inhibitors: treatment efficacy and safety profile in patients with psoriasis. J Immunol Res. 2014;2014:283617.

Nielsen OH, Seidelin JB, Ainsworth M, Coskun M. Will novel oral formulations change the management of inflammatory bowel disease? Expert Opin Investig Drugs. 2016;25:709–18.

Shuai K, Liu B. Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol. 2003;3:900–11.

Thomas SJ, Snowden JA, Zeidler MP, Danson SJ. The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br J Cancer. 2015;113(3):365–71.

SMAD7

Argollo M, Fiorino G, Hindryckx P, Peyrin-Biroulet L, Danese S. Novel therapeutic targets for inflammatory bowel disease. J Autoimmun. 2017;85:103–16.

Currò D, Pugliese D, Armuzzi A. Frontiers in drug research and development for inflammatory bowel disease. Front Pharmacol. 2017;8:400.

Nielsen OH, Seidelin JB, Ainsworth M, Coskun M. Will novel oral formulations change the management of inflammatory bowel disease? Expert Opin Investig Drugs. 2016;25:709–18.

Sphingosine 1-photspate

Argollo M, Fiorino G, Hindryckx P, Peyrin-Biroulet L, Danese S. Novel therapeutic targets for inflammatory bowel disease. J Autoimmun. 2017;85:103–16.

Currò D, Pugliese D, Armuzzi A. Frontiers in drug research and development for inflammatory bowel disease. Front Pharmacol. 2017;8:400.

Nielsen OH, Seidelin JB, Ainsworth M, Coskun M. Will novel oral formulations change the management of inflammatory bowel disease? Expert Opin Investig Drugs. 2016;25:709–18.

Tumour Necrosis Factor Alpha

Argollo M, Fiorino G, Hindryckx P, Peyrin-Biroulet L, Danese S. Novel therapeutic targets for inflammatory bowel disease. J Autoimmun. 2017;85:103–16.

Holleran G, Lopetuso L, Petito V, Graziani C, Ianiro G, McNamara D, et al.The innate and adaptive immune system as targets for biologic therapies in inflammatory bowel disease. Int J Mol Sci. 2017;18:E2020.

Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol. 2016;12:49–62.

Monteleone G, Pallone F, Caprioli F. Investigational cytokine-targeted therapies for ulcerative colitis. Expert Opin Investig Drugs. 2013;22:1123–32.

Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014;14:329–42.

Pedersen J, Coskun M, Soendergaard C, Salem M, Nielsen OH. Inflammatory pathways of importance for management of inflammatory bowel disease. World J Gastroenterol. 2014;20:64–77.

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