Epigenetic DNA Methylation of EBI3 Modulates Human Interleukin-35 Formation via NFkB Signaling: A Promising Therapeutic Option in Ulcerative Colitis

Ulcerative colitis (UC), a severe chronic disease with unclear etiology that is associated with increased risk for colorectal cancer, is accompanied by dysregulation of cytokines. Epstein–Barr virus-induced gene 3 (EBI3) encodes a subunit in the unique heterodimeric IL-12 cytokine family of either pro- or anti-inflammatory function. After having recently demonstrated that upregulation of EBI3 by histone acetylation alleviates disease symptoms in a dextran sulfate sodium (DSS)-treated mouse model of chronic colitis, we now aimed to examine a possible further epigenetic regulation of EBI3 by DNA methylation under inflammatory conditions. Treatment with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC) and TNFα led to synergistic upregulation of EBI3 in human colon epithelial cells (HCEC). Use of different signaling pathway inhibitors indicated NFκB signaling was necessary and proportional to the synergistic EBI3 induction. MALDI-TOF/MS and HPLC-ESI-MS/MS analysis of DAC/TNFα-treated HCEC identified IL-12p35 as the most probable binding partner to form a functional protein. EBI3/IL-12p35 heterodimers (IL-35) induce their own gene upregulation, something that was indeed observed in HCEC cultured with media from previously DAC/TNFα-treated HCEC. These results suggest that under inflammatory and demethylating conditions the upregulation of EBI3 results in the formation of anti-inflammatory IL-35, which might be considered as a therapeutic target in colitis.

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NLRP3-Dependent and -Independent Processing of Interleukin (IL)-1β in Active Ulcerative Colitis

International Journal of Molecular Sciences ◽

10.3390/ijms20010057 ◽

2018 ◽

Vol 20 (1) ◽

pp. 57 ◽

Cited By ~ 11

Author(s):

Nicole Ranson ◽

Mark Veldhuis ◽

Brent Mitchell ◽

Scott Fanning ◽

Anthony Cook ◽

...

Keyword(s):

Ulcerative Colitis ◽

Epithelial Cell ◽

Lamina Propria ◽

Immune Cells ◽

Cell Layer ◽

Therapeutic Option ◽

Spatial Relationship ◽

Inflammatory Conditions ◽

Epithelial Cell Layer ◽

Active Disease

A contributing factor in the development of ulcerative colitis (UC) and Crohn’s disease (CD) is the disruption of innate and adaptive signaling pathways due to aberrant cytokine production. The cytokine, interleukin (IL)-1β, is highly inflammatory and its production is tightly regulated through transcriptional control and both inflammasome-dependent and inflammasome- independent proteolytic cleavage. In this study, qRT-PCR, immunohistochemistry, immunofluorescence confocal microscopy were used to (1) assess the mRNA expression of NLRP3, IL-1β, CASP1 and ASC in paired biopsies from UC and CD patient, and (2) the colonic localization and spatial relationship of NLRP3 and IL-1β in active and quiescent disease. NLRP3 and IL-1β were found to be upregulated in active UC and CD. During active disease, IL-1β was localized to the infiltrate of lamina propria immune cells, which contrasts with the near-exclusive epithelial cell layer expression during non-inflammatory conditions. In active disease, NLRP3 was consistently expressed within the neutrophils and other immune cells of the lamina propria and absent from the epithelial cell layer. The disparity in spatial localization of IL-1β and NLRP3, observed only in active UC, which is characterized by a neutrophil-dominated lamina propria cell population, implies inflammasome-independent processing of IL-1β. Consistent with other acute inflammatory conditions, these results suggest that blocking both caspase-1 and neutrophil-derived serine proteases may provide an additional therapeutic option for treating active UC.

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Acute Myocardial Infarction Complicating Active Ulcerative Colitis: A Case Report

Case Reports in Cardiology ◽

10.1155/2011/876896 ◽

2011 ◽

Vol 2011 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Eva D. Papadimitraki ◽

Mubarak Ahamed ◽

Nicholas H. Bunce

Keyword(s):

Myocardial Infarction ◽

Ulcerative Colitis ◽

Acute Myocardial Infarction ◽

Myocardial Damage ◽

Chronic Inflammatory Disease ◽

Inflammatory Conditions ◽

Increased Risk ◽

Venous Thromboembolic ◽

Cardiac Manifestations

Ulcerative colitis (UC) is a chronic inflammatory disease that predominantly affects the gastrointestinal (GI) tract but can involve extraintestinal organs including musculoskeletal system and skin. The most frequent cardiac manifestations of UC are pericarditis and myocarditis. Patients display an increased risk for venous thromboembolic complications and mesenteric ischemia, but the association with ischemic heart disease and myocardial infarction is uncertain. We present the case of a 27-year-old man with anti-PRIII ANCA-positive ulcerative colitis and increased factor VIII activity who presented with an acute myocardial infarction. We discuss possible causative links between these clinical entities and demonstrate the role of cardiac magnetic resonance (CMR) in patients with underlying inflammatory conditions who present with chest pain and evidence of myocardial damage.

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Epigenetic histone modulation contributes to improvements in inflammatory bowel disease via EBI3

Cellular and Molecular Life Sciences ◽

10.1007/s00018-020-03451-9 ◽

2020 ◽

Vol 77 (23) ◽

pp. 5017-5030 ◽

Cited By ~ 1

Author(s):

Alexandra Wetzel ◽

Bettina Scholtka ◽

Christian Gerecke ◽

Burkhard Kleuser

Keyword(s):

Histone Acetylation ◽

Histone Deacetylase Inhibitors ◽

Therapeutic Option ◽

Human Colon ◽

Epigenetic Mechanism ◽

Local Formation ◽

Cytokine Levels ◽

Anti Inflammatory

Abstract Ulcerative colitis (UC) is characterized by relapsing–remitting inflammatory episodes paralleled by varying cytokine levels, suggesting that switching epigenetic processes might be involved. However, the epigenetic impact on cytokine levels in colitis is mostly unexplored. The heterodimeric interleukin (IL)-12 cytokine family have various functions in both pro- and anti-inflammatory processes. The family member IL-35 (EBI3/IL-12p35) was recently reported to play an anti-inflammatory role in UC. Therefore, we aimed to investigate a possible epigenetic regulation of the IL-35 subunits in vitro and in vivo, and to examine the epigenetic targeting of EBI3 expression as a therapeutic option for UC. Exposure to either the pro-inflammatory TNFα or to histone deacetylase inhibitors (HDACi) significantly increased EBI3 expression in Human Colon Epithelial Cells (HCEC) generated from healthy tissue. When applied in combination, a drastic upregulation of EBI3 expression occurred, suggesting a synergistic mechanism. Consequently, IL-35 was increased as well. In vivo, the intestines of HDACi-treated wild-type mice exhibited reduced pathological signs of colitis compared to non-treated colitic mice. However, the improvement by HDACi treatment was completely lost in Ebi3-deficient mice (Ebi3−/−). In fact, HDACi appeared to exacerbate the disease phenotype in Ebi3−/−. In conclusion, our results reveal that under inflammatory conditions, EBI3 is upregulated by the epigenetic mechanism of histone acetylation. The in vivo data show that the deficiency of EBI3 plays a key role in colitis manifestation. Concordantly, our data suggest that conditions promoting histone acetylation, such as upon HDACi application, improve colitis by a mechanism involving the local formation of the anti-inflammatory cytokine IL-35.

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DNA hypo-methylation facilitates anti-inflammatory responses in severe ulcerative colitis

PLoS ONE ◽

10.1371/journal.pone.0248905 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0248905

Author(s):

Hagar Taman ◽

Christopher G. Fenton ◽

Endre Anderssen ◽

Jon Florholmen ◽

Ruth H. Paulssen

Keyword(s):

Ulcerative Colitis ◽

Dna Methylation ◽

Disease Severity ◽

Inflammatory Responses ◽

Principal Component ◽

Severe Ulcerative Colitis ◽

Inflammatory Genes ◽

Genome Wide ◽

Treatment Naïve ◽

Anti Inflammatory

Severe ulcerative colitis (UC) is a potentially life-threatening disease with a potential colorectal cancer (CRC) risk. The aim of this study was to explore the relationship between transcriptomic and genome-wide DNA methylation profiles in a well-stratified, treatment-naïve severe UC patient population in order to define specific epigenetic changes that could be responsible for the grade of disease severity. Mucosal biopsies from treatment-naïve severe UC patients (n = 8), treatment-naïve mild UC (n = 8), and healthy controls (n = 8) underwent both whole transcriptome RNA-Seq and genome-wide DNA bisulfite- sequencing, and principal component analysis (PCA), cell deconvolutions and diverse statistical methods were applied to obtain a dataset of significantly differentially expressed genes (DEGs) with correlation to DNA methylation for severe UC. DNA hypo-methylation correlated with approximately 80% of all DEGs in severe UC when compared to mild UC. Enriched pathways of annotated hypo-methylated genes revealed neutrophil degranulation, and immuno-regulatory interactions of the lymphoid system. Specifically, hypo-methylated anti-inflammatory genes found for severe UC were IL10, SIGLEC5, CD86, CLMP and members of inflammasomes NLRP3 and NLRC4. Hypo-methylation of anti-inflammatory genes during severe UC implies an interplay between the epithelium and lamina propria in order to mitigate inflammation in the gut. The specifically DNA hypo-methylated genes found for severe UC can potentially be useful biomarkers for determining disease severity and in the development of new targeted treatment strategies for severe UC patients.

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Mean Platelet Volume (MPV): New Perspectives for an Old Marker in the Course and Prognosis of Inflammatory Conditions

Mediators of Inflammation ◽

10.1155/2019/9213074 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 34

Author(s):

Aleksandra Korniluk ◽

Olga Martyna Koper-Lenkiewicz ◽

Joanna Kamińska ◽

Halina Kemona ◽

Violetta Dymicka-Piekarska

Keyword(s):

Ulcerative Colitis ◽

Cardiovascular Diseases ◽

Mean Platelet Volume ◽

Cerebral Stroke ◽

Platelet Volume ◽

Neoplastic Diseases ◽

Risk Of Death ◽

Inflammatory Conditions ◽

Pubmed Database ◽

Increased Risk

Platelet size has been demonstrated to reflect platelet activity and seems to be a useful predictive and prognostic biomarker of cardiovascular events. It is associated with a variety of prothrombotic and proinflammatory diseases. The aim is a review of literature reports concerning changes in the mean platelet volume (MPV) and its possible role as a biomarker in inflammatory processes and neoplastic diseases. PubMed database was searched for sources using the following keywords: platelet activation, platelet count, mean platelet volume and: inflammation, cancer/tumor, cardiovascular diseases, myocardial infarction, diabetes, lupus disease, rheumatoid arthritis, tuberculosis, ulcerative colitis, renal disease, pulmonary disease, influencing factors, age, gender, genetic factors, oral contraceptives, smoking, lifestyle, methods, standardization, and hematological analyzer. Preference was given to the sources which were published within the past 20 years. Increased MPV was observed in cardiovascular diseases, cerebral stroke, respiratory diseases, chronic renal failure, intestine diseases, rheumatoid diseases, diabetes, and various cancers. Decreased MPV was noted in tuberculosis during disease exacerbation, ulcerative colitis, SLE in adult, and different neoplastic diseases. The study of MPV can provide important information on the course and prognosis in many inflammatory conditions. Therefore, from the clinical point of view, it would be interesting to establish an MPV cut-off value indicating the intensity of inflammatory process, presence of the disease, increased risk of disease development, increased risk of thrombotic complications, increased risk of death, and patient’s response on applied treatment. Nevertheless, this aspect of MPV evaluation allowing its use in clinical practice is limited and requires further studies.

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Incidence, Clinical Features, Management, and Prevention of Herpes Zoster in Patients Receiving Antitumor Necrosis Factor Therapy: A Clinical Review

Journal of Cutaneous Medicine and Surgery ◽

10.1177/1203475420914622 ◽

2020 ◽

Vol 24 (3) ◽

pp. 278-284

Author(s):

Byung-Soo Kim ◽

Emanual Maverakis ◽

Clarie Alexanian ◽

Jenny Z. Wang ◽

Siba P. Raychaudhuri

Keyword(s):

Herpes Zoster ◽

Clinical Features ◽

Viral Infections ◽

Therapeutic Option ◽

Tnf Inhibitors ◽

Tnf Inhibitor ◽

Inflammatory Conditions ◽

Increased Risk ◽

Factor Therapy ◽

Necrosis Factor

Tumor necrosis factor (TNF) inhibitors have been used as an excellent therapeutic option in a variety of chronic inflammatory conditions. However, a recognized significant adverse effect of TNF inhibitor therapy is the increased risk of infections. The influence of TNF inhibitors on the course of coexisting or newly developed viral infections has not been extensively investigated. Therefore, we reviewed the recent publications to highlight the incidence, clinical features, management, and prevention of herpes zoster in patients who are receiving TNF inhibitors.

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Induction of remission with tacrolimus in a patient with severe acute, cortisone refractory ulcerative colitis and severe Covid-19 pneumonia: a case report

BMC Gastroenterology ◽

10.1186/s12876-022-02094-3 ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Lisanne Rieker ◽

Johannes Hofer ◽

Golo Petzold ◽

Volker Ellenrieder ◽

Ahmad Amanzada

Keyword(s):

Ulcerative Colitis ◽

Viral Infections ◽

Clinical Symptoms ◽

Therapeutic Option ◽

Viral Reactivation ◽

High Dose ◽

Increased Risk ◽

Tacrolimus Therapy ◽

Dose Oral ◽

History Of

Abstract Background Therapy regimens used in patients with inflammatory Bowel Disease (IBD) have been associated with enhanced risk of viral infections or viral reactivation. Moreover, it is uncertain whether IBD patients have increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or infected patients may have an increased risk for severe coronavirus disease 2019 (Covid-19). Managing severe acute flare in ulcerative colitis during the Covid-19 pandemic is a challenge for clinicians and their patients. The results of the published studies mainly report on the role of the prior medication, but not how to treat severe acute flare of IBD patients with severe Covid-19 pneumonia. Case presentation We report the case of a 68-year-old patient with a long history of ulcerative colitis. He was initially admitted to an external hospital because of severe acute flare. The initiation of a high-dose oral cortisone therapy did not improve the clinical symptoms. During the inpatient treatment, he was tested positive for SARS-CoV-2. At admission to our hospital the patient showed severe flare of his ulcerative colitis and increased Covid-19 symptoms. A cortisone-refractory course was noticed. After detailed multidisciplinary risk–benefit assessment, we initiated an intravenous tacrolimus therapy and dose of prednisolone was tapered gradually. After clinical response, the therapy was adjusted to infliximab. Additionally, the Covid-19 pneumonia was kept under control despite immunosuppression and the patient could be discharged in clinical remission. Conclusions This case suggest the use of tacrolimus as a bridging therapeutic option for severe acute, cortisone refractory ulcerative colitis in Covid-19 patients. Nevertheless, the best treatment strategy for IBD patients presenting a flare during the outbreak has yet to be defined. Further data for IBD patients under calcineurin inhibitor therapy are urgently needed.

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