Targeting JAK-STAT signal transduction in IBD

Soendergaard, Christoffer; Bergenheim, Fredrik; Bjerrum, Jacob Tveiten; Nielsen, Ole Haagen

doi:10.1016/j.pharmthera.2018.07.003

Cited by 77 publications

(61 citation statements)

References 96 publications

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“…We evaluated the effects of Bry‐1 on the intestinal mucosal immune response and found that Bry‐1 treatment decreased the Th17 and Th1 responses and increased the Treg response in Il‐10 −/− mice. Next, we focused on STAT signalling, as this pathway has a key role in regulating T cell‐mediated immune responses in human CD . We found that p‐STAT3 and p‐STAT4 expression decreased with Bry‐1 treatment in Il‐10 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

Bryostatin‐1 ameliorated experimental colitis in Il‐10^−/− Mice by protecting the intestinal barrier and limiting immune dysfunction

Zuo

et al. 2019

J Cellular Molecular Medi

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Bryostatin‐1 (Bry‐1) has been proven to be effective and safe in clinical trials of a variety of immune‐related diseases. However, little is known about its effect on Crohn's disease (CD). We aimed to investigate the impact of Bry‐1 on CD‐like colitis and determine the mechanism underlying this effect. In the present study, 15‐week‐old male Il‐10 −/− mice with spontaneous colitis were divided into positive control and Bry‐1‐treated (Bry‐1, 30 μg/kg every other day, injected intraperitoneally for 4 weeks) groups. Age‐matched, male wild‐type (WT) mice were used as a negative control. The effects of Bry‐1 on colitis, intestinal barrier function and T cell responses as well as the potential regulatory mechanisms were evaluated. We found that the systemic delivery of Bry‐1 significantly ameliorated colitis in Il‐10 −/− mice, as demonstrated by decreases in the disease activity index (DAI), inflammatory score and proinflammatory mediator levels. The protective effects of Bry‐1 on CD‐like colitis included the maintenance of intestinal barrier integrity and the helper T cell (Th)/regulatory T cell (Treg) balance. These effects of Bry‐1 may act in part through nuclear factor erythroid 2‐related factor 2 (Nrf2) signalling activation and STAT3/4 signalling inhibition. The protective effect of Bry‐1 on CD‐like colitis suggests Bry‐1 has therapeutic potential in human CD, particularly given the established clinical safety of Bry‐1.

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Section: Discussionmentioning

confidence: 99%

Bryostatin‐1 ameliorated experimental colitis in Il‐10^−/− Mice by protecting the intestinal barrier and limiting immune dysfunction

Zuo

et al. 2019

J Cellular Molecular Medi

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“…This study showed the first evidence for potential clinical efficacy and safety of a selective JAK1 inhibitor for the treatment of active CD [49]. Filgotinib might represent a new oral treatment to induce remission in patients with CD, but a phase III study will still be necessary [42]. According to Soendergaard et al, a combined phase IIb/III randomized, placebo-controlled study with filgotinib for the treatment of moderate-to-severe UC (the SELECTION1 study) is ongoing.…”

Section: Jak Inhibitorsmentioning

confidence: 97%

“…Tofacitinib (CP-690,550), a first-class JAK360 inhibitor, works by inhibiting JAK1/JAK3 and has a lower side effect on JAK2 and TYK2 [41]. This JAK inhibitor was tested in clinical trials to verify its potential treatment for some immune system disorders, including CD and UC [42].…”

Section: Jak Inhibitorsmentioning

confidence: 99%

Anti-Integrins, Anti-Interleukin 12/23p40, and JAK Inhibitors for the Inflammatory Bowel Disease Treatment

Steigleder¹,

Neto²,

Nagasako³

et al. 2020

Biological Therapy for Inflammatory Bowel Disease

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Inflammatory bowel diseases (IBD) present a broad inflammatory cascade that is sometimes difficult to control. Patients with ulcerative colitis (UC) and Crohn's disease (CD) are exposed to intense and harmful effects that compromise their quality of life. There is a constant need for new classes of drugs that act on different fronts of inflammation control. Initially, biologics revolutionized inflammatory bowel disease treatment. Anti-tumor necrosis factor (anti-TNF) agents and infliximab, followed by adalimumab and certolizumab pegol, have been proven to induce clinical and endoscopic remission. However, some patients are primary nonresponders, and a significant proportion of initial responders lose response throughout the treatment. The emergence of new therapies, such as anti-integrins, anti-interleukins, and inhibitors of Janus kinase (JAK), can become an alternative option for patients with previous therapeutic failures, besides offering greater safety than other biological therapies up to now. Among anti-integrins, vedolizumab is the drug with proven efficacy in both induction and maintenance of remission and has local and selective action in the intestine. Ustekinumab represents the group of anti-interleukins, acting to control interleukin-12 (IL12) and interleukin-23 (IL23). JAK inhibitors (tofacitinib) act on intracellular inflammatory mediators and have the advantage of being orally administered.

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“…Janus kinase inhibitors have been developed and evaluated in clinical trials. In 2018, tofacitinib was approved by the FDA and EMA for the treatment of ulcerative colitis [ 152 ]. Recently, a small-molecule inhibitor of Tyk2 blocked IL-23 signaling in vitro and inhibited disease progression in animal models of spondyloarthritis (SpA, [ 153 ]).…”

Section: Conclusion and Perspectives For New Targeting Strategiesmentioning

confidence: 99%

IL-12 and IL-23—Close Relatives with Structural Homologies but Distinct Immunological Functions

Floß

Moll

Scheller

2020

Cells

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Cytokines of the IL-12 family show structural similarities but have distinct functions in the immune system. Prominent members of this cytokine family are the pro-inflammatory cytokines IL-12 and IL-23. These two cytokines share cytokine subunits and receptor chains but have different functions in autoimmune diseases, cancer and infections. Accordingly, structural knowledge about receptor complex formation is essential for the development of new therapeutic strategies preventing and/or inhibiting cytokine:receptor interaction. In addition, intracellular signaling cascades can be targeted to inhibit cytokine-mediated effects. Single nucleotide polymorphisms can lead to alteration in the amino acid sequence and thereby influencing protein functions or protein–protein interactions. To understand the biology of IL-12 and IL-23 and to establish efficient targeting strategies structural knowledge about cytokines and respective receptors is crucial. A highly efficient therapy might be a combination of different drugs targeting extracellular cytokine:receptor assembly and intracellular signaling pathways.

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Targeting JAK-STAT signal transduction in IBD

Cited by 77 publications

References 96 publications

Bryostatin‐1 ameliorated experimental colitis in Il‐10^−/− Mice by protecting the intestinal barrier and limiting immune dysfunction

Bryostatin‐1 ameliorated experimental colitis in Il‐10^−/− Mice by protecting the intestinal barrier and limiting immune dysfunction

Anti-Integrins, Anti-Interleukin 12/23p40, and JAK Inhibitors for the Inflammatory Bowel Disease Treatment

IL-12 and IL-23—Close Relatives with Structural Homologies but Distinct Immunological Functions

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Targeting JAK-STAT signal transduction in IBD

Cited by 77 publications

References 96 publications

Bryostatin‐1 ameliorated experimental colitis in Il‐10−/− Mice by protecting the intestinal barrier and limiting immune dysfunction

Bryostatin‐1 ameliorated experimental colitis in Il‐10−/− Mice by protecting the intestinal barrier and limiting immune dysfunction

Anti-Integrins, Anti-Interleukin 12/23p40, and JAK Inhibitors for the Inflammatory Bowel Disease Treatment

IL-12 and IL-23—Close Relatives with Structural Homologies but Distinct Immunological Functions

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Bryostatin‐1 ameliorated experimental colitis in Il‐10^−/− Mice by protecting the intestinal barrier and limiting immune dysfunction

Bryostatin‐1 ameliorated experimental colitis in Il‐10^−/− Mice by protecting the intestinal barrier and limiting immune dysfunction