Elsevier

Pharmacological Reports

Volume 68, Issue 4, August 2016, Pages 789-796
Pharmacological Reports

Review article
Janus kinases in inflammatory bowel disease: Four kinases for multiple purposes

https://doi.org/10.1016/j.pharep.2016.04.001Get rights and content

Abstract

Inflammatory bowel disease (IBD) comprises mainly Crohn's disease and ulcerative colitis. These pathologies are characterized by inflammation of the gut and destruction of its epithelium. Many cytokines play key roles in this pathology. They are generally involved in the inflammatory process but also display anti-inflammatory activities and some regulate the gut epithelium homeostasis, constituting therapeutic targets for IBD. Many of these cytokines signal through the JAK/STAT pathway and thus, JAKs represent also very promising therapeutic targets and selective or non-selective inhibitors of these kinases have already been assayed in clinical trials with various success. The existence of four JAKs and six STAT factors that are used in combination make these pathways complex enough to generate various responses. Here we summarize the role of the JAKs in some cytokines involved in IBD. The multifunctional role they play through the various functions of the cytokines they signal for makes difficult the anticipation of the effective beneficial role that JAK inhibitors may have.

Introduction

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a class of intestinal disease characterized by chronic and relapsing inflammation of the gastrointestinal (GI) tract. It is a growing worldwide health-care problem with a continually increasing incidence [1]. The exact etiology of UC and CD is still unknown, but it is considered that the origin of the disease involves a combination of genetic and environmental factors, immune dysregulation, barrier dysfunction and changes in the intestinal microbiome. The current consensus on the pathogenesis of IBD is that the disease develops and gradually evolves to a chronic state as a consequence of an inappropriate response of the immune system to the microbiome in genetically predisposed individuals exposed to particular environmental factors [2]. While being part of the same class of pathologies, UC and CD display remarkable differences at the level of signs and symptoms. CD affects any part of the GI tract, from mouth to rectum in a non-continuous manner and generally causes transmural inflammation. It is frequently associated with complications such as strictures, fistulas and abscesses [3]. In contrast, UC is characterized by a mucosal inflammation which is limited to the colon [4].

The essential role of inflammation in the development of UC and CD is extensively supported by the efficacy of treatments that impact the immune system. This however must not mask the importance of the integrity of the epithelial barrier that separates microbiome and the sentinels of the immune system. Of interest, many cytokines play a key role in the pathophysiology of IBD by their pro-inflammatory or anti-inflammatory roles, some of which also impact the integrity or defence of the epithelial barrier [5]. The Janus kinases (JAK) play a key role in the signaling of several of these cytokines and therefore constitute attractive potential therapeutic targets. As little direct evidence of JAK-related effects in IBD is known, the importance of JAKS in IBD will be indirectly analyzed based on the role of several cytokines in the IBD pathogenesis, thereby highlighting the multifaceted roles these kinases can fulfill.

Section snippets

JAK mode of action

The JAKs are tyrosine kinases that constitute a family of four proteins, JAK1, JAK2, JAK3 and TYK2. While JAK3 is mainly expressed in myeloid and hematopoietic cells, the three other JAKs are widely expressed. They function as pairs, as a relay between the receptors for cytokines of growth factors and the STAT (Signal Transducer and Activator of Transcription) factors. Upon direct phosphorylation by the JAKs, STATs migrate to the nucleus as dimers to stimulate transcription of the target genes

Conclusions and perspectives

Treatment of IBD requires both a reduction of the inflammation through an appropriate regulation of the immune system while allowing a recovery activity on the intestinal epithelium. The JAKs, through their involvement in the signaling of many cytokines and growth factors, are particularly well placed to fulfill this role. However, the pleiotropy of their effects also carries a risk. As for gut homeostasis, the best JAK inhibitor will have to slow down the immune system while favoring, or at

Conflict of interest

René Galien is an employee of Galapagos SASU.

Funding body

Work performed at Galapagos by the author was funded by the company Galapagos.

Acknowledgements

The author would like to thank all colleagues at Galapagos and in the scientific community for fruitful and constructive discussions.

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