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.
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 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
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.
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
A focus on selectivity may be key to UC-associated inflammation.14
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.
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NV.
© 2021 Galapagos NV. All rights reserved.
GL-UC-FIL-202105-00003 08/21
GALAPAGOS and the GALAPAGOS logo are registered or pending trademarks of Galapagos
NV.
© 2021 Galapagos NV. All rights reserved.
GL-UC-FIL-202105-00003 08/21
© Copyright 2021 Galapagos NV
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