Enhancer of zeste homolog 2 contributes to apoptosis by inactivating janus kinase 2/ signal transducer and activator of transcription signaling in inflammatory bowel disease

Abstract Background With the approval of tofacitinib, an oral Janus Kinase (JAK) inhibitor, modulation of kinase activity has been added to the therapeutic armamentarium of inflammatory bowel disease (IBD). Despite its established efficacy, at least a third of patients will not respond to this or other therapeutic options such as anti-tumour necrosis factor (TNF), anti-interleukin (IL)23/IL12 compounds or vedolizumab. A better understanding of the inflammatory profile could aid in tailoring drugs to individual patients. We therefore explored mucosal cytokine, chemokine and kinase activity profiles in IBD. Methods Colonic mucosal biopsies were collected from (1) patients with Crohn’s disease (CD, N = 8), (2) patients with ulcerative colitis (UC, N = 8) and (3) healthy controls (N = 4). IBD samples were collected both from inflamed and non-inflamed tissue from the same patients. All IBD patients were biological-naïve and had not used corticosteroids in the past 3 months. Biopsies were snap frozen for later kinase activity determination or directly used in a 24-h explant culture. Whole biopsy kinase activity (tyrosine, serine and threonine kinases) was assessed using the Pamgene platform. A 64-analyte panel was examined in the supernatant of the cultured biopsies employing a multiplex assay (Luminex). Results Whole-biopsy kinase activity differed between inflamed and non-inflamed mucosa of IBD patients, with more overall tyrosine kinase activity in inflamed mucosa in UC, and serine/threonine kinase activity in inflamed mucosa in CD as compared with non-inflamed mucosa (Figure 1). The kinase activity profile of non-inflamed mucosa of CD and UC patients was similarly different from mucosa of healthy control participants (Figure 2). The cytokine and chemokine profile of inflamed biopsies differed from non-inflamed IBD biopsies and healthy control biopsies, with higher levels of S100A8, TNFα, IL-6, oncostatin M (OSM) and triggering receptor expressed on myeloid cells-1 (TREM-1), amongst others (Figure 3). Conclusion In IBD, inflammation in the mucosa can be characterised both by explant-culture and kinase activity assessment. The difference in kinase activity between non-inflamed IBD mucosa and healthy control mucosa suggests the presence of sub-clinical alterations in cell signalling. The observed differences in the kinase, cytokine and chemokine profiles underscore the importance of this approach in the elucidation of the pathophysiology in IBD.

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Tofacitinib in Patients with Ulcerative Colitis: Inflammatory Bowel Disease Questionnaire Items in Phase 3 Randomized Controlled Induction Studies

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa193 ◽

2020 ◽

Author(s):

Marla C Dubinsky ◽

Marco DiBonaventura ◽

Haiyun Fan ◽

Andrew G Bushmakin ◽

Joseph C Cappelleri ◽

...

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Janus Kinase ◽

Effect Sizes ◽

Phase 3 ◽

Inflammatory Bowel Disease Questionnaire ◽

Bowel Symptoms ◽

Inflammatory Bowel ◽

Disease Questionnaire

Abstract Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We examined the effect of tofacitinib induction treatment on Inflammatory Bowel Disease Questionnaire (IBDQ) items in adults with moderate to severe UC. Methods Data were pooled from the randomized, 8‑week, double-blind, phase 3 OCTAVE Induction 1 and 2 studies. The IBDQ was self-administered by patients at baseline, week 4, and week 8, with higher scores indicating better health-related quality of life (HRQoL). Change from baseline in IBDQ items was analyzed for 10 mg of tofacitinib twice daily (BID) vs placebo using a linear mixed-effects model, with no multiplicity adjustment performed. Effect sizes were calculated. Subgroup analyses by tumor necrosis factor inhibitor (TNFi) experience were performed. Results Significant improvements (nominal P < 0.05) were observed in all IBDQ items with 10 mg of tofacitinib BID vs placebo at weeks 4 and 8. For the overall population, the largest treatment differences across all items were reported for “bowel movements been loose” at weeks 4 and 8, and “problem with rectal bleeding” at week 8 (mean treatment differences all 1.1; both in bowel symptoms domain). These items also showed the largest effect sizes. Treatment benefits were generally slightly numerically higher in TNFi-experienced vs TNFi-naïve patients. Conclusions Tofacitinib induction therapy improved all IBDQ items vs placebo in patients with UC, reflecting improvements in HRQoL, with greatest benefits reported in bowel symptoms domain items (Funded by Pfizer Inc; OCTAVE Induction 1 and OCTAVE Induction 2; ClinicalTrials.gov, NCT01465763 and NCT01458951, respectively).

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Cardiovascular Risk Assessment and Impact of Medications on Cardiovascular Disease in Inflammatory Bowel Disease

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa258 ◽

2020 ◽

Author(s):

Preetika Sinh ◽

Raymond Cross

Keyword(s):

Heart Failure ◽

Cardiovascular Disease ◽

Inflammatory Bowel Disease ◽

Cardiovascular Risk ◽

Lupus Erythematosus ◽

Bowel Disease ◽

Severe Heart Failure ◽

Janus Kinase ◽

Increased Risk ◽

Inflammatory Bowel

Abstract There is increased risk of cardiovascular disease in patients with chronic inflammatory disorders such as rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. Studies have shown association between cardiovascular disease (eg, myocardial infarction, heart failure, stroke) and inflammatory bowel disease. Medications such as infliximab and adalimumab (monoclonal antibodies to tumor necrosis factor α) may help decrease the inflammatory burden and cardiovascular risk; however, there have been reports of hypertriglyceridemia and worsening of moderate to severe heart failure with these medications. Janus kinase inhibitors, such as tofacitinib, have been associated with hyperlipidemia and thromboembolism. We aim to discuss clinical and imaging modalities to assess cardiovascular risk in inflammatory bowel disease patients and review the role of various medications with respect to cardiovascular disease in this population.

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Anticolitic Effect of Viscum coloratum through Suppression of Mast Cell Activation

The American Journal of Chinese Medicine ◽

10.1142/s0192415x19500101 ◽

2019 ◽

Vol 47 (01) ◽

pp. 203-221 ◽

Cited By ~ 5

Author(s):

Jae-Myung Yoo ◽

Kwang Il Park ◽

Jin Yeul Ma

Keyword(s):

Inflammatory Bowel Disease ◽

Mast Cell ◽

Bowel Disease ◽

Immunoglobulin E ◽

Janus Kinase ◽

Mast Cell Activation ◽

Matrix Metalloprotease ◽

Zonula Occludens ◽

Inflammatory Bowel ◽

Zonula Occludens 1

Viscum coloratum has been used as a component for traditional medicine for therapy of inflammatory diseases. Nonetheless, effect of Viscum coloratum on inflammatory bowel disease is unknown. Therefore, we investigated whether the ethanol extract of Viscum coloratum (VCE) could suppress inflammatory responses in dextran sodium sulfate (DSS)-treated mice and mast cell-derived inflammatory mediator (MDIM)-activated Caco-2 cells. VCE significantly attenuated body weight loss, shortened colon length, enteric epithelium disruption, enterorrhagia and colonic edema in DSS-treated mice. Additionally, VCE decreased the levels of immunoglobulin E, interleukin-6 and tumor necrosis factor-[Formula: see text] in serum and the activity of myeloperoxidase in colonic tissue. Moreover, VCE inhibited the infiltration of immune cells as well as the activity and expression of both matrix metalloprotease-2 and matrix metalloprotease-9. Furthermore, VCE restored zonula occludens-1 expression. Consistent with in vivo studies, VCE suppressed the activity and expression of matrix metalloprotease-2 and matrix metalloprotease-9 in MDIM-activated Caco-2 cells. In addition, VCE reinstated the expression of zonula occludens-1 through inhibiting activation of janus kinase 2/signal transducer and activator of transcription 3 in the cells. In conclusion, VCE exerts anticolitic action through inhibiting the activation of mast cells. Therefore, VCE may be useful as a phytomedicine or functional food for inflammatory bowel disease.

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Signal transducer and activator of transcription 6 gene G2964A polymorphism and inflammatory bowel disease

Clinical & Experimental Immunology ◽

10.1046/j.1365-2249.2003.02079.x ◽

2003 ◽

Vol 131 (3) ◽

pp. 446-450 ◽

Cited By ~ 21

Author(s):

B. XIA ◽

J. B. A. CRUSIUS ◽

J. WU ◽

A. ZWIERS ◽

A. A. VAN BODEGRAVEN ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Signal Transducer ◽

Inflammatory Bowel

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Clinical Pharmacology of Janus Kinase Inhibitors in Inflammatory Bowel Disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjaa014 ◽

2020 ◽

Vol 14 (Supplement_2) ◽

pp. S725-S736 ◽

Cited By ~ 3

Author(s):

Pavine L C Lefevre ◽

Niels Vande Casteele

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Clinical Pharmacology ◽

Gastrointestinal Tract ◽

Bowel Disease ◽

Kinase Inhibitors ◽

Response To Therapy ◽

Janus Kinase ◽

Janus Kinase Inhibitors ◽

Inflammatory Bowel

Abstract Inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, are chronic inflammatory disorders of the gastrointestinal tract which are characterised, in part, by an imbalance in the production of several pro- and anti-inflammatory cytokines. Although various agents are effective for inducing and maintaining remission, approximately 20% of patients are treatment-refractory and require surgery. Parenterally administered monoclonal antibody-based biologics are associated with adverse effects resulting in treatment discontinuation and/or immunogenicity, leading to loss of response to therapy. Approximately 50% of patients who initially respond to treatment with tumour necrosis factor antagonists lose response to therapy within the 1st year of treatment. Incidence of immunogenicity tends to decrease over time, but once present can persist for years, even after treatment discontinuation. Nonimmunogenic oral small molecule therapies, including Janus kinase inhibitors, are currently being developed and have demonstrated efficacy in early phase clinical trials, which has already led to regulatory approval of tofacitinib for the treatment of patients with moderate-to-severe ulcerative colitis. Differentiation of T cells into T helper cells, which are mediators of the inflammatory response in inflammatory bowel disease, is mediated by the Janus kinase signal transducer and activator of the transcription signalling pathway. Absorption and distribution of Janus kinase inhibitors occurs at the site of action in the gastrointestinal tract, and newer compounds are being developed with limited systemic absorption, potentially reducing the risk of adverse effects. The current review describes the clinical pharmacology of approved Janus kinase inhibitors, as well as those in clinical development for the treatment of inflammatory bowel disease.

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Advances in the Development of Janus Kinase Inhibitors in Inflammatory Bowel Disease: Future Prospects

Drugs ◽

10.1007/s40265-017-0755-8 ◽

2017 ◽

Vol 77 (10) ◽

pp. 1057-1068 ◽

Cited By ~ 22

Author(s):

Mathurin Flamant ◽

Josselin Rigaill ◽

Stephane Paul ◽

Xavier Roblin

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Kinase Inhibitors ◽

Janus Kinase ◽

Future Prospects ◽

Janus Kinase Inhibitors ◽

Inflammatory Bowel

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Selective Tyrosine Kinase 2 Inhibition for Treatment of Inflammatory Bowel Disease: New Hope on the Rise

Inflammatory Bowel Diseases ◽

10.1093/ibd/izab135 ◽

2021 ◽

Author(s):

Silvio Danese ◽

Laurent Peyrin-Biroulet

Keyword(s):

Inflammatory Bowel Disease ◽

Tyrosine Kinase ◽

Bowel Disease ◽

Inflammatory Diseases ◽

Janus Kinase ◽

Type I ◽

Tyrosine Kinase 2 ◽

Immune Mediated ◽

Inflammatory Bowel

Abstract Conventional systemic and biologic agents are the mainstay of inflammatory bowel disease (IBD) management; however, many of these agents are associated with loss of clinical response, highlighting the need for effective, novel targeted therapies. Janus kinase (JAK) 1-3 and tyrosine kinase 2 (TYK2) mediate signal transduction events downstream of multiple cytokine receptors that regulate targeted gene transcription, including the interleukin-12, interleukin-23, and type I interferon receptors for TYK2. This review summarizes the role of TYK2 signaling in IBD pathogenesis, the differential selectivity of TYK2 inhibitors, and the potential clinical implications of TYK2 inhibition in IBD. A PubMed literature review was conducted to identify studies of JAK1-3 and TYK2 inhibitors in IBD and other immune-mediated inflammatory diseases. Key efficacy and safety information was extracted and summarized. Pan-JAK inhibitors provide inconsistent efficacy in patients with IBD and are associated with toxicities resulting from a lack of selectivity at therapeutic dosages. Selective inhibition of TYK2 signaling via an allosteric mechanism, with an agent that binds to the regulatory (pseudokinase) domain, may reduce potential toxicities typically associated with JAK1-3 inhibitors. Deucravacitinib, a novel, oral, selective TYK2 inhibitor, and brepocitinib and PF-06826647, TYK2 inhibitors that bind to the active site in the catalytic domain, are in development for IBD and other immune-mediated inflammatory diseases. Allosteric TYK2 inhibition is more selective than JAK1-3 inhibition and has the potential to limit toxicities typically associated with JAK1-3 inhibitors. Future studies will be important in establishing the role of selective, allosteric TYK2 inhibition in the management of IBD.

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The Future of Janus Kinase Inhibitors in Inflammatory Bowel Disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjx003 ◽

2017 ◽

Vol 11 (7) ◽

pp. 885-893 ◽

Cited By ~ 44

Author(s):

L.C.S. De Vries ◽

M.E. Wildenberg ◽

W.J. De Jonge ◽

G.R. D’Haens

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Kinase Inhibitors ◽

Janus Kinase ◽

Janus Kinase Inhibitors ◽

The Future ◽

Inflammatory Bowel

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JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00311.2015 ◽

2016 ◽

Vol 310 (3) ◽

pp. G155-G162 ◽

Cited By ~ 68

Author(s):

Silvio Danese ◽

Matthew Grisham ◽

Jennifer Hodge ◽

Jean-Baptiste Telliez

Keyword(s):

Inflammatory Bowel Disease ◽

Inflammatory Cytokines ◽

Bowel Disease ◽

Unmet Need ◽

Janus Kinase ◽

Prolonged Treatment ◽

Cytokine Signaling ◽

Jak Inhibitor ◽

Adaptive Immune ◽

Inflammatory Bowel

The inflammatory diseases ulcerative colitis and Crohn's disease constitute the two main forms of inflammatory bowel disease (IBD). They are characterized by chronic, relapsing inflammation of the gastrointestinal tract, significantly impacting on patient quality of life and often requiring prolonged treatment. Existing therapies for IBD are not effective for all patients, and an unmet need exists for additional therapies to induce and maintain remission. Here we describe the mechanism of action of the Janus kinase (JAK) inhibitor, tofacitinib, for the treatment of IBD and the effect of JAK inhibition on the chronic cycle of inflammation that is characteristic of the disease. The pathogenesis of IBD involves a dysfunctional response from the innate and adaptive immune system, resulting in overexpression of multiple inflammatory cytokines, many of which signal through JAKs. Thus JAK inhibition allows multiple cytokine signaling pathways to be targeted and is expected to modulate the innate and adaptive immune response in IBD, thereby interrupting the cycle of inflammation. Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated as a targeted immunomodulator for IBD. Clinical development of tofacitinib and other JAK inhibitors is ongoing, with the aspiration of providing new treatment options for IBD that have the potential to deliver prolonged efficacy and clinically meaningful patient benefits.

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