STAT1 epigenetically regulates LCP2 and TNFAIP2 by recruiting EP300 to contribute to the pathogenesis of inflammatory bowel disease

Abstract Background The aetiology of inflammatory bowel disease (IBD) is related to genetics and epigenetics. Epigenetic regulation of the pathogenesis of IBD has not been well defined. Here, we investigated the role of H3K27ac events in the pathogenesis of IBD. Based on previous ChIP-seq and RNA-seq assays, we studied signal transducer and activator of transcription 1 (STAT1) as a transcription factor (TF) and investigated whether the STAT1–EP300–H3K27ac axis contributes to the development of IBD. We performed ChIP-PCR to investigate the interaction between STAT1 and H3K27ac, and co-IP assays were performed to investigate the crosstalk between STAT1 and EP300. Results Lymphocyte cytosolic protein 2 (LCP2) and TNF-α‐inducible protein 2 (TNFAIP2) are target genes of STAT1. p-STAT1 binds to the enhancer loci of the two genes where H3K27ac is enriched, and EP300 subsequently binds to regulate their expression. In mice with dextran sulfate sodium (DSS)-induced acute colitis, an EP300 inhibitor significantly inhibited colitis. Conclusions p-STAT1 and EP300 promote TNFAIP2 and LCP2 expression through an increase in H3K27ac enrichment on their enhancers and contribute to the pathogenesis of chronic inflammation. Graphic abstract

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Role of the C5a receptor (C5aR) in acute and chronic dextran sulfate-induced models of inflammatory bowel disease

Inflammatory Bowel Diseases ◽

10.1002/ibd.21012 ◽

2009 ◽

Vol 15 (12) ◽

pp. 1812-1823 ◽

Cited By ~ 39

Author(s):

Kay Johswich ◽

Myriam Martin ◽

André Bleich ◽

Michael Kracht ◽

Oliver Dittrich-Breiholz ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Dextran Sulfate ◽

C5a Receptor ◽

Inflammatory Bowel

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The role of the complement and contact systems in the dextran sulfate sodium-induced colitis model: the effect of C1 inhibitor in inflammatory bowel disease

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00400.2009 ◽

2010 ◽

Vol 298 (6) ◽

pp. G878-G883 ◽

Cited By ~ 22

Author(s):

Fengxin Lu ◽

Stacey M. Fernandes ◽

Alvin E. Davis

Keyword(s):

Inflammatory Bowel Disease ◽

Weight Loss ◽

Bowel Disease ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Activity Index ◽

Complement C3 ◽

C1 Inhibitor ◽

Inflammatory Bowel

The complement and contact systems may be involved in the pathophysiological process of inflammatory bowel disease (IBD). C1 inhibitor (C1INH) is the most important inhibitor of both the complement and contact systems. We evaluated the role of these systems and the effect of both active and inactive forms of C1INH (iC1INH) in dextran sulfate sodium (DSS)-induced colitis mouse model. Three percent DSS was used in drinking water to induce colitis in complement C3-deficient (C3−/−) mice, bradykinin type 2 receptor deficient (Bk2R−/−) mice, and C57BL/6 mice. After ten days DSS exposure, C3−/− mice exhibited markedly less weight loss than wild-type (WT) mice (12 ± 3.3% vs. 30 ± 1.2%, P < 0.05) and developed a milder disease-activity index (DAI), histological score, colon shortening, and myeloperoxidase (MPO) elevation ( P < 0.05, respectively). The Bk2R−/− mice were not protected from the disease. Seven-day treatment with either native C1INH or iC1INH reduced the severity of the disease in WT mice, as indicated by decreased weight loss (15 ± 1.8%, 14 ± 2.1% vs. 30 ± 1.2%, P < 0.05, respectively), DAI, intestinal tissue damage, and MPO elevation compared with untreated WT DSS control mice ( P < 0.05, respectively). These findings suggest that complement plays a role in the development of DSS-induced colitis and that blockade of the complement system might be useful for the acute phase of IBD treatment. C1INH, however, leads to an amelioration of DSS-induced colitis via a mechanism that does not involve the inhibition of complement or contact system activation but does result in significant suppression of leukocyte infiltration.

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Tu1734 A Role of iRhom2 for the Secretion of TNF-α in Inflammatory Bowel Disease

Gastroenterology ◽

10.1016/s0016-5085(14)63010-9 ◽

2014 ◽

Vol 146 (5) ◽

pp. S-829 ◽

Cited By ~ 1

Author(s):

Sung Wook Hwang ◽

Jaeyoung Chun ◽

Changhyun Lee ◽

Jong Pil Im ◽

Joo Sung Kim

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Tnf Α ◽

Inflammatory Bowel

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Immunomodulatory role of Parkinson’s disease 7 in inflammatory bowel disease

Scientific Reports ◽

10.1038/s41598-021-93671-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rita Lippai ◽

Apor Veres-Székely ◽

Erna Sziksz ◽

Yoichiro Iwakura ◽

Domonkos Pap ◽

...

Keyword(s):

Parkinson’S Disease ◽

Inflammatory Bowel Disease ◽

Parkinson's Disease ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Tnf Α ◽

Inflammatory Bowel ◽

Ht 29

AbstractRecently the role of Parkinson’s disease 7 (PARK7) was studied in gastrointestinal diseases, however, the complex role of PARK7 in the intestinal inflammation is still not completely clear. Expression and localization of PARK7 were determined in the colon biopsies of children with inflammatory bowel disease (IBD), in the colon of dextran sodium sulphate (DSS) treated mice and in HT-29 colonic epithelial cells treated with interleukin (IL)-17, hydrogen peroxide (H2O2), tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β or lipopolysaccharide (LPS). Effect of PARK7 on the synthesis of IBD related cytokines was determined using PARK7 gene silenced HT-29 cells and 3,4,5-trimethoxy-N-(4-(8-methylimidazo(1,2-a)pyridine-2-yl)phenyl)benzamide (Comp23)—compound increasing PARK7 activity—treated mice with DSS-colitis. PARK7 expression was higher in the mucosa of children with Crohn’s disease compared to that of controls. While H2O2 and IL-17 treatment increased, LPS, TNF-α or TGF-β treatment decreased the PARK7 synthesis of HT-29 cells. PARK7 gene silencing influenced the synthesis of IL1B, IL6, TNFA and TGFB1 in vitro. Comp23 treatment attenuated the ex vivo permeability of colonic sacs, the clinical symptoms, and mucosal expression of Tgfb1, Il1b, Il6 and Il10 of DSS-treated mice. Our study revealed the role of PARK7 in the regulation of IBD-related inflammation in vitro and in vivo, suggesting its importance as a future therapeutic target.

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Role of leptin and TNF-α in energy metabolism regulation in patients with inflammatory bowel disease

Digestive and Liver Disease ◽

10.1016/s1590-8658(00)80199-1 ◽

2000 ◽

Vol 32 ◽

pp. A39

Author(s):

E. Capristo ◽

G. Addolorato ◽

A. Scarfone ◽

G. Valentini ◽

G. Mingrone ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Energy Metabolism ◽

Bowel Disease ◽

Metabolism Regulation ◽

Tnf Α ◽

Inflammatory Bowel

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Cytokines in canine inflammatory bowel disease

Polish Journal of Veterinary Sciences ◽

10.2478/pjvs-2013-0025 ◽

2013 ◽

Vol 16 (1) ◽

pp. 165-171 ◽

Cited By ~ 13

Author(s):

A. Kołodziejska-Sawerska ◽

A. Rychlik ◽

A. Depta ◽

M. Wdowiak ◽

M. Nowicki ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Mrna Expression ◽

Lamina Propria ◽

Bowel Disease ◽

Unknown Etiology ◽

Tnf Α ◽

Chronic Enteropathies ◽

Inflammatory Bowel ◽

Ifn Γ

Abstract Canine inflammatory bowel disease is a group of chronic enteropathies characterized by persistent or recurring gastric symptoms with an unknown etiology which are related to histopathological changes in the mucosa of the small and large bowel in the form of cellular infiltration in the mucosal lamina propria. Recent years have witnessed a growing number of investigations into the role of the immune system and, in particular, cytokines in the development of IBD. In this article, the expression of pro-inflammatory (IL-1, IL-2, IL-5, IL-6, IL-12, IL-18, IFN-γ, TNF-α) and anti-inflammatory cytokines (IL-4, IL-10) was compared in canine patients with IBD based on clinical presentation, breed, lamina propria cell infiltrate and histopathological grade. Only selected studies confirmed higher mRNA expression levels of cytokines IL-2, IL-4, IL-5, IL-12p40, IFN-γ, TNF-α and TGF-β in dogs with IBD in comparison with healthy subjects. GSD were strongly represented in most study populations. Dogs with LPE were characterized by elevated levels of IL-1α, IL-1β, IL-2, IL-5, IL-6, IL-12, TNF-α, TGF-β. The present studies of canine patients with LPC revealed the mRNA expression of cytokines IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p35, IL-12p40, IFN-γ, TNF-α, TGF-β. In the reviewed studies, the progression of IBD was not accompanied by changes in the mRNA expression of IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-18, TNF-α, IFN-γ or TGF-β.

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Preventive Effects of Mallotus japonicus Cortex Extracts on Dextran Sulfate Sodium-Induced Ulcerative Colitis in C57 BL/6J Mice

The Natural Products Journal ◽

10.2174/2210315509666191106112622 ◽

2020 ◽

Vol 10 (2) ◽

pp. 177-185

Author(s):

Yoshiyuki Kimura

Keyword(s):

Inflammatory Bowel Disease ◽

Blood Cell ◽

Red Blood Cell ◽

Bowel Disease ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Eosinophil Infiltration ◽

Mucosal Membrane ◽

Tnf Α ◽

Inflammatory Bowel

Background: The cortex of Mallotus japonicus (Euphorbiaceae) has traditionally been used to treat gastric ulcers, duodenal ulcers, and gastric hyperacidity in Japan. A large number of studies have recently focused on its effects on Inflammatory Bowel Disease (IBD). Objective: The aim of the present study was to examine the effects of M. japonicus (MJ) extracts on large intestinal diarrhea and inflammation using Inflammatory Bowel Disease (IBD) mouse models. Methods: The present study used 3% Dextran Sulfate Sodium (DSS)-treated colitis models. Red blood cell, platelet, and leukocyte counts in addition to hematocrit (Ht), hemoglobin (Hb), and colonic cytokine and chemokine levels were measured in DSS-treated C57BL/6J mice during the experimental period. Results: The Disease Activity Index (DAI) was lower in 3% DSS-treated mice orally administered MJ (200 and 500 mg/kg) than in mice administered 3% DSS only. Furthermore, MJ inhibited decreases in red blood cell and platelet counts as well as Hb and Ht levels in DSS-treated mice. Colon histology using direct fast scarlet staining revealed that MJ prevented mucosal membrane ulceration and eosinophil infiltration of the mucosal membrane induced by the DSS treatment. Increases in colonic Monocyte Chemoattractant Protein 1 (MCP)-1, interleukin (IL)-1β, and Tumor Necrosis Factor (TNF)-α levels in DSS-treated mice were reduced by orally administered MJ extracts. Conclusion: The present results suggest that M. japonicus cortex extracts are an effective treatment for IBD through the inhibition of increases in colonic IL-1β, TNF-α, and MCP-1 levels and eosinophil infiltration of the colon in DSS-treated mice.

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Role of TNFR-related 2 mediated immune responses in dextran sulfate sodium-induced inflammatory bowel disease

Molecules and Cells ◽

10.1007/s10059-011-0013-y ◽

2011 ◽

Vol 31 (2) ◽

pp. 99-104 ◽

Cited By ~ 12

Author(s):

Woon-Ki Kim ◽

Jin-Soo Park ◽

Ok-Ju Sul ◽

Jae-Hee Seo ◽

Byum-Kyu Choi ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Immune Responses ◽

Bowel Disease ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Inflammatory Bowel

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The Effect of Dietary Glutathione and Coenzyme Q10 on the Prevention and Treatment of Inflammatory Bowel Disease in Mice

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831.74.1.74 ◽

2004 ◽

Vol 74 (1) ◽

pp. 74-85 ◽

Cited By ~ 5

Author(s):

Liu ◽

Russell ◽

Smith ◽

Bronson ◽

Milbury ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Dextran Sulfate ◽

Coenzyme Q ◽

Histological Evaluation ◽

Therapeutic Effects ◽

Prevention Study ◽

Prevention And Treatment ◽

Inflammatory Bowel ◽

Pre Treatment

Because reactive oxygen species have been implicated as mediators of inflammatory bowel disease (IBD), we evaluated the potential preventive and therapeutic effects of two dietary antioxidants, glutathione (GSH) and coenzyme Q10 (CoQ10) on dextran sulfate sodium (DSS)-induced colitis in mice. Fifty female 8-wk old Swiss-Webster mice were randomly assigned to 4 groups for a pre-treatment 'prevention' study: (1) GSH (1% of diet); (2) CoQ10 (200 mg/kg/d); (3) DSS only (3% of drinking water); (4) control (no treatment). The mice in groups 1 and 2 were fed with GSH or CoQ10 for 21 wks, and the mice in groups 1, 2 and 3 were provided DSS from wk 7 for 4 cycles (1 cycle = 1 wk DSS followed by 2-wk water). Another 50 mice were randomly assigned to 4 groups for a 21-wk 'treatment' study where the mice in groups 1, 2, and 3 were administered DSS for 6 cycles (18 wks) to induce colitis. GSH and CoQ10 were added from wk 7 until the completion of the protocol. Loose stools and hemocult positivity were modestly but significantly reduced with GSH or CoQ10 at several periods during the intervention in both the prevention and treatment studies. In contrast, histological evaluation revealed increases in colonic dysplasia and ulceration with GSH or CoQ10. Thus, in this mouse model, GSH and CoQ10 appear to have a beneficial effect on acute signs of IBD, but may have an adverse impact on the chronic pathophysiology of the disease. Further studies using additional animal models are required to determine whether GSH or CoQ10 provide a favorable or unfavorable benefit:risk ratio in the prevention or treatment of IBD.

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