UC pathogenesis and the JAK-STAT pathway

Four JAK proteins form pairs that mediate cytokine signalling — JAK1, JAK2, JAK3, and TYK2.4,5

Multiple cytokines signal through the JAK-STAT pathway by binding to their associated receptors.2,4,5

The JAK-STAT pathway represents a point of convergence common to multiple pathways of inflammation.2,6

References:
  1. Coskun M, Salem M, Pedersen J, Nielsen OH. Pharmacol Res. 2013;76:1-8.
  2. Fernández-Clotet A, Castro-Poceiro J, Panés J. Curr Pharm Des. 2019;25(1):32-40.
  3. Neurath MF. Nat Rev Immunol. 2014;14(5):329-342.
  4. O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. Annu Rev Med. 2015;66:311-328.
  5. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea JJ. Nat Rev Drug Discov. 2017;16(12):843-862.
  6. Salas A, Hernandez-Rocha C, Duijvestein M, et al. Nat Rev Gastroenterol Hepatol. 2020;17(6):323-337.

JAK pairings

Normal cytokine signalling through JAK-containing protein complexes mediates essential functions, such as haematopoiesis and immunity against pathogens.1,2

Depending on which JAK pairs are activated, downstream effects may vary.1,3

In UC, excessive signalling through the JAK-STAT pathway results in aberrant cytokine production and a cycle of chronic, relapsing inflammation and potential damage.1,3

Downstream effects of JAK-STAT pathway activation: In health and disease

Selective JAK Pairings That Mediate Cytokine Signalling JAK1 and JAK3
IBD Pathogenesis*

  • Inflammation4
  • Deleterious impact on wound healing5
  • Pro-inflammatory cytokine production in mucosa, tumour development6
Normal Physiology*

  • Lymphocyte proliferation and homeostasis13,14
  • Adaptive immune response, intestinal homeostasis9
  • Humoural immunity, mucus production, anti-helminth defence14
Selective JAK Pairings That Mediate Cytokine Signalling JAK1, JAK2, TYK2
IBD Pathogenesis*

  • Chronic intestinal epithelial inflammation5,7
  • Pro-inflammatory cytokine production5
  • Increased permeability of intestinal epithelial barrier5,8,9
  • Intestinal epithelial cell apoptosis and ulceration8,10
  • Epithelial cell proliferation and tumour growth (colorectal carcinogenesis)7,10,11
Normal Physiology*

  • T-cell differentiation and inflammation3
  • Wound healing5
  • Defence from extracellular pathogens14
  • Lipid metabolism15
Selective JAK Pairings That Mediate Cytokine Signalling JAK1 and JAK2
IBD Pathogenesis*

  • Epithelial cell death7
  • Disruption and loss of epithelial barrier function10
Normal Physiology*

  • Antiviral and antimicrobial immunity14,15
  • Epithelial barrier protection5,16
  • Homeostasis of mucosal surfaces16
Selective JAK Pairings That Mediate Cytokine Signalling JAK2 and JAK2
IBD Pathogenesis*

  • Not applicable
Normal Physiology*

  • Erythropoiesis, myelopoiesis, and platelet production17
  • Growth15
  • Intestinal epithelium protection5
Selective JAK Pairings That Mediate Cytokine Signalling JAK1 and TYK2
IBD Pathogenesis*

  • IBD susceptibility12
  • Pro-inflammatory cytokine production6
Normal Physiology*

  • Antiviral, antitumour defences14,15
  • Epithelial regeneration and maintenance of intestinal barrier5,9
Selective JAK Pairings That Mediate Cytokine Signalling IBD Pathogenesis* Normal Physiology*
JAK1 and JAK3
  • Inflammation4
  • Deleterious impact on wound healing5
  • Pro-inflammatory cytokine production in mucosa, tumour development6
  • Lymphocyte proliferation and homeostasis13,14
  • Adaptive immune response, intestinal homeostasis9
  • Humoural immunity, mucus production, anti-helminth defence14
JAK1, JAK2, TYK2
  • Chronic intestinal epithelial inflammation5,7
  • Pro-inflammatory cytokine production5
  • Increased permeability of intestinal epithelial barrier5,8,9
  • Intestinal epithelial cell apoptosis and ulceration8,10
  • Epithelial cell proliferation and tumour growth (colorectal carcinogenesis)7,10,11
  • T-cell differentiation and inflammation3
  • Wound healing5
  • Defence from extracellular pathogens14
  • Lipid metabolism15
JAK1 and JAK2
  • Epithelial cell death7
  • Disruption and loss of epithelial barrier function10
  • Antiviral and antimicrobial immunity14,15
  • Epithelial barrier protection5,16
  • Homeostasis of mucosal surfaces16
JAK2 and JAK2
  • Not applicable
  • Erythropoiesis, myelopoiesis, and platelet production17
  • Growth15
  • Intestinal epithelium protection5
JAK1 and TYK2
  • IBD susceptibility12
  • Pro-inflammatory cytokine production6
  • Antiviral, antitumour defences14,15
  • Epithelial regeneration and maintenance of intestinal barrier5,9

* The physiological processes listed here are examples of the unique JAK roles and do not provide an exhaustive list.

JAK1 pairs are involved in pro-inflammatory cytokine signalling implicated in UC pathology.7

JAK2 pairs are important for normal blood cell production.17

References:
  1. Coskun M, Salem M, Pedersen J, Nielsen OH. Pharmacol Res. 2013;76:1-8.
  2. Virtanen AT, Haikarainen T, Raivola J, Silvennoinen O. Bio Drugs. 2019;33(1):15-32.
  3. Fernández-Clotet A, Castro-Poceiro J, Panés J. Curr Pharm Des. 2019;25(1):32-40.
  4. Clark JD, Flanagan ME, Telliez JB. J Med Chem. 2014;57(12):5023-5038.
  5. Flamant M, Rigaill J, Paul S, Roblin X. Drugs. 2017;77(10):1057-1068.
  6. Neurath MF. Cytokine Growth Factor Rev. 2019;45:1-8.
  7. Neurath MF. Nat Rev Immunol. 2014;14(5):329-342.
  8. De Vries LCS, Ludbrook VJ, Hicks KJ, D’Haens GR. BMJ Case Rep. 2017; pii: bcr-2017-221078.
  9. Soendergaard C, Bergenheim FH, Bjerrum JT, Nielsen OH. Pharmacol Ther. 2018;192:100-111.
  10. Bevivino G, Monteleone G. Expert Rev Gastroenterol Hepatol. 2018;12(9):907-915.
  11. Lee SH, Kwon JE, Cho ML. Intest Res. 2018;16(1):26-42.
  12. Mizoguchi A, Yano A, Himuro H, Ezaki Y, Sadanaga T, Mizoguchi E. J Gastroenterol. 2018;53(4):465-474.
  13. O’Shea JJ, Murray PJ. Immunity. 2008;28(4):477-487.
  14. Heneghan AF, Pierre JF, Kudsk KA. JAK-STAT. 2013;2(4):e25530.
  15. Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. Drugs. 2017;77(5):521-546.
  16. Abraham C, Dulai PS, Vermeire S, Sandborn WJ. Gastroenterology. 2017;152(2):374-388.e4.
  17. O’Shea JJ, Plenge R. Immunity. 2012;36(4):542-550.

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.2-7

 

The importance of JAK-STAT pathway signalling

Excessive cytokine signalling icon Excessive cytokine signalling

In UC, aberrant and excessive cytokine signalling via certain JAK pairings cause subclinical or acute mucosal inflammation that, if unresolved, leads to chronic intestinal inflammation induced by uncontrolled activation of the immune system.7

Deficient cytokine signalling icon Deficient cytokine signalling

Deficient cytokine signalling via certain JAK pairings can lead to disruption of essential physiological and immunological 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.3,8

Multiple pathways to inflammation in UC

  • There are multiple cytokine-driven inflammatory pathways implicated in the pathogenesis of IBD9
  • Simultaneous targeting of multiple cytokines has been shown to be an effective strategy for the management of this disease9
  • Many of the pro-inflammatory cytokines implicated in UC signal through JAK1-containing pairs6,10
  • Cytokines implicated in UC pathogenesis such as IL-33 that do not signal directly through JAK1-containing pairs are still directly associated with the activity of JAK1-dependent cytokines such as IL-4 and IFNγ11

JAK1 is involved in multiple cytokine pathways6,12

Diagram showing JAK1’s involvement in multiple cytokine pathways

Associated with the broadest cytokine profile among the JAK proteins, JAK1 pairs function in several signalling pathways and have the potential to modulate the activity of multiple cytokines.10

Not all JAK1-associated cytokines are included here. This is not an exhaustive list.
IFN, interferon; IL, interleukin; LIF, leukemia inhibitory factor; OSM, oncostatin M.

Regulation of the JAK-STAT pathway

JAK1 icon JAK1 is involved in multiple signalling pathways and can have an impact on many of the cytokines involved in UC.10
JAK3 icon JAK3 is expressed mainly in haematopoietic cells and plays a key role in the development of cells of the immune system.13
JAK2 icon JAK2 is largely restricted to cells that are important for normal blood cell production, and its activity must be maintained to avoid haematological effects.8,12

While modulation of JAK-STAT activity has the potential to affect a wide range of inflammatory processes, it is important to preserve homeostatic, noninflammatory pathways to avoid complications.10,13

Selective modulation of JAK1-containing pairs in the JAK-STAT pathway may have the potential to reduce the inflammation of UC without compromising normal pathway functions.6

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

 

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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