Ulcerative Colitis

JAK-STAT Function

Introduction

JAK-STAT pathway activity is essential for normal immunological function1


Essential immunological functions depend on the dynamic equilibrium of the JAK-STAT pathway.1
Deficient or excessive JAK-STAT pathway signalling has been associated with physiological disruptions and
inflammation, respectively.

Disrupted Equilibrium

The importance of JAK-STAT pathway signalling




In UC, atypical and excessive cytokine signalling via certain JAK pairings causes acute or subclinical mucosal inflammation that can lead to chronic intestinal inflammation induced by uncontrolled activation of the immune system.7





Deficient cytokine signalling via certain JAK pairings can lead to disruption of essential immunological and physiological functions.2-6,8                                                                                                                                                                        

Understanding the JAK-STAT pathway and its role in essential functions may help to advance the research
of inflammatory diseases, such as UC.

Multiple pathways to inflammation in UC

   • Multiple proinflammatory cytokine pathways are implicated in the pathogenesis of UC9
   • Simultaneous targeting of multiple cytokines has demonstrated efficacy for the management of UC9
   • Many of the proinflammatory cytokines implicated in UC signal through JAK1-containing protein complexes6,10
   • Cytokines implicated in UC pathogenesis that do not signal directly through JAK1, such as IL-33, are still directly
     associated with the activity of JAK1-dependent cytokines, such as IL-4 and IFNγ11

JAK Profiles

JAK1 is involved in multiple cytokine pathways6,12

Not all JAK1-, JAK2-, JAK3-, or TYK2-associated cytokines are included here. This is not an exhaustive list.
EPO, erythropoeitin; G-CSF, granulocyte colony-stimulating factor; GH, growth hormone; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; LIF, leukemia inhibitory factor; OSM, oncostatin M; TPO, thrombopoeitin.

JAK Activity

Regulation of the JAK-STAT pathway

While modulation of JAK-STAT activity could potentially affect a wide range of inflammatory processes,
preservation of homeostatic, noninflammatory pathways is important to avoid complications.10,13

Preferential modulation of JAK1-containing protein complexes in the JAK-STAT pathway may reduce the inflammation of UC without compromising normal pathway functions.6,*

A focus on selectivity may be key to UC-associated inflammation.14

Related

JAK Pairings

Learn more about the roles of different JAK pairs.

IBD, inflammatory bowel disease; IFN, interferon; IL, interleukin; JAK, Janus kinase; STAT, signal transducer and activator of transcription; TYK, tyrosine kinase; UC, ulcerative colitis.

* Note that some of the observations pertaining to these potential benefits were described in mouse studies.


REFERENCES: 1.Villarino AV, Kanno Y, Ferdinand JR, O'Shea JJ. J Immunol. 2015;194(1):21-27. 2. Wang KS, Zom E, Ritz J. Blood. 2001;97(12):3860-3866. 3. Coskun M, Salem M, Pedersen J, Nielsen OH. Pharmacol Res. 2013;76:1-8. 4. Bottos A, Gotthardt D, Gill JW, et al. Nat Commun. 2016;7:12258. 5. Gotthardt D, Sexl V. Front Immunol. 2017;7:694. 6. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ. Nat Rev Drug Discov. 2017;16(12):843-862. 7. Neurath MF. Nat Rev Immunol. 2014;14(5):329-342. 8. O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. Annu Rev Med. 2015;66:311-328. 9. Danese S, Argollo M, Le Berre C, Peyrin-Biroulet L. Gut. 2019;68(10):1893-1899. 10. Virtanen AT, Haikarainen T, Raivola J, Silvennoinen O. BioDrugs. 2019;33(1):15-32. 11. Pinto SM, Subbannayya Y, Rex DAB, et al. J Cell Commun Signal. 2018;12(3):615-624. 12. Salas A, Hernandez-Rocha C, Duijvestein M, et al. Nat Rev Gastroenterol Hepatol. 2020;17(6):323-337. 13. Flamant M, Rigaill J, Paul S, Roblin X. Drugs. 2017;77(10):1057-1068. 14. Fernández-Clotet A, Castro-Poceiro J, Panés J. Curr Pharm Des. 2019;25(1):32-40.