Mild Chronic Colitis Triggers Parkinsonism in LRRK2 Mutant Mice Through Activating TNF ‐α Pathway

2021 ◽  
Author(s):  
Chin‐Hsien Lin ◽  
Han‐Yi Lin ◽  
En‐Pong Ho ◽  
Yi‐Ci Ke ◽  
Mei‐Fang Cheng ◽  
...  
Keyword(s):  
Mutant Mice ◽  
Chronic Colitis ◽  
Tnf Α

scholarly journals Chronic colitis-induced visceral pain is associated with increased anxiety during quiescent phase

2019 ◽  
Vol 316 (6) ◽  
pp. G692-G700 ◽  
Author(s):  
Emmeline Salameh ◽  
Mathieu Meleine ◽  
Guillaume Gourcerol ◽  
Jean-Claude do Rego ◽  
Jean-Luc do Rego ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Visceral Pain ◽  
Myeloperoxidase Activity ◽  
Therapeutic Approaches ◽  
Chronic Colitis ◽  
Functional Symptoms ◽  
Tnf Α ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Novel Therapeutic

Inflammatory bowel diseases (IBD) are characterized by repetition of flares and remission periods leading to chronic postinflammatory sequelae. Among postinflammatory sequelae, one-third of patients with IBD are suffering from functional symptoms or psychological comorbidities that persist during remission. The aim of our study was to assess functional and behavioral sequelae of chronic colitis in rats with quiescent intestinal inflammation. Chronic colitis was induced by a weekly intrarectal injection of increasing concentrations of trinitrobenzene sulfonic acid (TNBS) for 3 wk (15–45 mg of TNBS) in 30 rats, whereas the control rats ( n = 24) received the vehicle. At 50 days post-TNBS, visceral sensitivity was assessed by visceromotor response to colorectal distension, and transient receptor potential vanilloid type 1 (TRPV1) expression was also quantified in the colon and dorsal root ganglia. Barrier function and inflammatory response were assessed by studying intestinal permeability, tight junction protein, myeloperoxidase activity, histological score, and cytokine production (IL-6, IL-10, and TNF-α). Anxiety behavioral tests were performed from 50 to 64 days after the last TNBS injection. Chronic TNBS induced 1) a visceral hypersensitivity ( P = 0.03), 2) an increased colon weight-to-length ratio ( P = 0.01), 3) higher inflammatory and fibrosis scores ( P = 0.0390 and P = 0.0016, respectively), and 4) a higher colonic IL-6 and IL-10 production ( P = 0.008 and P = 0.005, respectively) compared with control rats. Intestinal permeability, colonic production of TNF-α, myeloperoxidase activity, and TRPV1 expression did not differ among groups. Chronic TNBS increased anxiety-related behavior in the open-field test and in the acoustic stress test. In conclusion, chronic colitis induced functional sequelae such as visceral hypersensitivity and increased anxiety with a low-grade intestinal inflammation. Development of a representative animal model will allow defining novel therapeutic approaches to achieve a better management of IBD-related sequelae.NEW & NOTEWORTHY Patients with inflammatory bowel diseases have impaired quality of life. Therapeutic progress to control mucosal inflammation provides us an opportunity to develop novel approaches to understand mechanisms behind postinflammatory sequelae. We used a chronic colitis model to study long-term sequelae on visceral pain, gut barrier function, and psychological impact. Chronic colitis induced functional symptoms and increased anxiety in the remission period. It might define novel therapeutic approaches to achieve a better inflammatory bowel disease-related sequelae management.

Therapeutic effect of anti-OX40L and anti-TNF-α MAbs in a murine model of chronic colitis

2003 ◽  
Vol 284 (4) ◽  
pp. G595-G603 ◽  
Author(s):  
T. Totsuka ◽  
T. Kanai ◽  
K. Uraushihara ◽  
R. Iiyama ◽  
M. Yamazaki ◽  
...  
Keyword(s):  
T Cells ◽  
Crohn’S Disease ◽  
T Cell ◽  
Crohn's Disease ◽  
Lamina Propria ◽  
Therapeutic Effect ◽  
Therapeutic Effects ◽  
Chronic Colitis ◽  
Tnf Α ◽  
Ifn Γ

Interaction of OX40 (CD134) on T cells with its ligand (OX40L) on antigen-presenting cells has been implicated in pathogenic T cell activation. This study was performed to explore the involvement of OX40/OX40L in the development of T cell-mediated chronic colitis. We evaluated both the preventive and therapeutic effects of neutralizing anti-OX40L MAb on the development of chronic colitis in SCID mice induced by adoptive transfer of CD4+CD45RBhighT cells as an animal model of Crohn's disease. We also assessed the combination of anti-OX40L and anti-TNF-α MAbs to improve the therapeutic effect. Administration of anti-OX40L MAb markedly ameliorated the clinical and histopathological disease in preventive and therapeutic protocols. In vivo treatment with anti-OX40L MAb decreased CD4+T cell infiltration in the colon and suppressed IFN-γ, IL-2, and TNF-α production by lamina propria CD4+T cells. The combination with anti-TNF-α MAb further improved the therapeutic effect by abolishing IFN-γ, IL-2, and TNF-α production by lamina propria CD4+T cells. Our present results suggested a pivotal role of OX40/OX40L in the pathogenesis of T cell-mediated chronic colitis. The OX40L blockade, especially in combination with the TNF-α blockade, may be a promising strategy for therapeutic intervention of Crohn's disease.

RNAi-mediated silencing of TNF-α converting enzyme to down-regulate soluble TNF-α production for treatment of acute and chronic colitis

2016 ◽  
Vol 239 ◽  
pp. 231-241 ◽  
Author(s):  
Yoonsung Song ◽  
Ye-Ram Kim ◽  
So Mi Kim ◽  
Qurrat Ul Ain ◽  
Kiseok Jang ◽  
...  
Keyword(s):  
Converting Enzyme ◽  
Chronic Colitis ◽  
Tnf Α

Novel Histone Deacetylase 6 Inhibitor CKD-506 Inhibits NF-κB Signaling in Intestinal Epithelial Cells and Macrophages and Ameliorates Acute and Chronic Murine Colitis

2020 ◽  
Vol 26 (6) ◽  
pp. 852-862 ◽  
Author(s):  
Jung Won Lee ◽  
Soung-Min Lee ◽  
Jaeyoung Chun ◽  
Jong Pil Im ◽  
Su-Kil Seo ◽  
...  
Keyword(s):  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Histone Deacetylase 6 ◽  
Chronic Colitis ◽  
Acute Colitis ◽  
Murine Colitis ◽  
Tnf Α ◽  
Inflammatory Bowel ◽  
Iκbα Phosphorylation ◽  
Colitis Model

Abstract Background Selective blocking of HDAC6 has become a promising strategy in treating inflammatory bowel disease. CKD-506 is a novel isoform-selective inhibitor of histone deacetylase 6. The present study was performed to evaluate the effect of CKD-506 on the NF-κB signaling pathway in intestinal epithelial cells (IECs) and macrophages and on murine models of acute and chronic colitis. Methods RAW264RAW264.7 murine macrophages and COLO 205 human IECs were pretreated with CKD-506 and then stimulated with lipopolysaccharides (LPS). Cytokine expression of TNF-α, interleukin (IL)-6, IL-8, and IL-10 was measured by ELISA. The effect of CKD-506 on NF-κB signaling was evaluated by Western blotting of IκBα phosphorylation/degradation and electrophoretic mobility shift assay. In vivo studies were performed using a dextran sulfate sodium (DSS)–induced acute colitis model, a chronic colitis model in IL-10 knockout mice, and an adoptive transfer model. Colitis was quantified by the disease activity index, colon length, and histopathologic evaluation. Results CKD-506 suppressed the expression of pro-inflammatory cytokines such as IL-6, IL-8, and TNF-α in IECs and macrophages. CKD-506 strongly inhibited IκBα phosphorylation/degradation and the DNA-binding activity of NF-κB. Oral administration of CKD-506 attenuated DSS-induced acute colitis and chronic colitis in IL-10-/- and adoptive transfer models. CKD-506 ameliorated weight loss, disease activity, and histopathologic score in colitis mice and downregulated IκBα phosphorylation and pro-inflammatory cytokine production significantly. Conclusions CKD-506 blocked NF-κB signaling in IECs and macrophages and ameliorated experimental acute and chronic murine colitis models, which suggests that CKD-506 is a promising candidate for inflammatory bowel disease treatment as a small molecular medicine.

scholarly journals Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling

2005 ◽  
Vol 201 (3) ◽  
pp. 333-339 ◽  
Author(s):  
Hisaaki Shinohara ◽  
Akane Inoue ◽  
Noriko Toyama-Sorimachi ◽  
Yoshinori Nagai ◽  
Tomoharu Yasuda ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Tyrosine Phosphorylation ◽  
Map Kinases ◽  
Adaptor Proteins ◽  
Mutant Mice ◽  
Poly I:C ◽  
Negative Regulators ◽  
Erk Activation ◽  
Cpg Oligodeoxynucleotides ◽  
Tnf Α

Endotoxin, a bacterial lipopolysaccharide (LPS), causes fatal septic shock via Toll-like receptor (TLR)4 on effector cells of innate immunity like macrophages, where it activates nuclear factor κB (NF-κB) and mitogen-activated protein (MAP) kinases to induce proinflammatory cytokines such as tumor necrosis factor (TNF)-α. Dok-1 and Dok-2 are adaptor proteins that negatively regulate Ras–Erk signaling downstream of protein tyrosine kinases (PTKs). Here, we demonstrate that LPS rapidly induced the tyrosine phosphorylation and adaptor function of these proteins. The stimulation with LPS of macrophages from mice lacking Dok-1 or Dok-2 induced elevated Erk activation, but not the other MAP kinases or NF-κB, resulting in hyperproduction of TNF-α and nitric oxide. Furthermore, the mutant mice showed hyperproduction of TNF-α and hypersensitivity to LPS. However, macrophages from these mutant mice reacted normally to other pathogenic molecules, CpG oligodeoxynucleotides, poly(I:C) ribonucleotides, or Pam3CSK4 lipopeptide, which activated cognate TLRs but induced no tyrosine phosphorylation of Dok-1 or Dok-2. Forced expression of either adaptor, but not a mutant having a Tyr/Phe substitution, in macrophages inhibited LPS-induced Erk activation and TNF-α production. Thus, Dok-1 and Dok-2 are essential negative regulators downstream of TLR4, implying a novel PTK-dependent pathway in innate immunity.

scholarly journals Effects of octreotide treatment on early TNF-α production and localization in experimental chronic colitis

1999 ◽  
Vol 13 (5) ◽  
pp. 583-594 ◽  
Author(s):  
LAMRANI ◽  
TULLIEZ ◽  
L CHAUVELOT-MOACHON ◽  
CHAUSSADE ◽  
MAUPRIVEZ ◽  
...  
Keyword(s):  
Chronic Colitis ◽  
Tnf Α ◽  
Octreotide Treatment

Consumption of a baked corn and bean snack reduced chronic colitis inflammation in CD-1 mice via downregulation of IL-1 receptor, TLR, and TNF-α associated pathways

2020 ◽  
Vol 132 ◽  
pp. 109097 ◽  
Author(s):  
Ivan Luzardo-Ocampo ◽  
Rocio Campos-Vega ◽  
Elvira Gonzalez de Mejia ◽  
Guadalupe Loarca-Piña
Keyword(s):  
Chronic Colitis ◽  
Tnf Α

Spontaneous Chronic Colitis in TCRα-Mutant Mice; an Experimental Model of Human Ulcerative Colitis

2000 ◽  
Vol 19 (1) ◽  
pp. 123-138 ◽  
Author(s):  
Atul K. Bhan ◽  
Emiko Mizoguchi ◽  
Rex Neal Smith ◽  
Atsushi Mizoguchi
Keyword(s):  
Ulcerative Colitis ◽  
Experimental Model ◽  
Mutant Mice ◽  
Chronic Colitis

scholarly journals Role of inducible nitric oxide synthase in the regulation of VCAM-1 expression in gut inflammation

1999 ◽  
Vol 277 (3) ◽  
pp. G572-G576 ◽  
Author(s):  
Shigeyuki Kawachi ◽  
Adam Cockrell ◽  
F. Stephen Laroux ◽  
Laura Gray ◽  
D. Neil Granger ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Wild Type ◽  
Chronic Colitis ◽  
Antibody Technique ◽  
Tnf Α ◽  
Factor Α ◽  
Oxide Synthase

The objectives of this study were to assess the role of the inducible isoform of nitric oxide synthase (iNOS) on vascular cell adhesion molecule 1 (VCAM-1) expression in vivo in an acute model of inflammation induced in iNOS-deficient (iNOS−/−) mice and compare these data to those obtained by pharmacological inhibition of iNOS in a CD4+ T lymphocyte-dependent model of chronic colitis. VCAM-1 expression was quantified in vivo using the dual radiolabel monoclonal antibody technique. We found that intraperitoneal injection of 10 μg/kg tumor necrosis factor-α (TNF-α) enhanced VCAM-1 expression by approximately twofold in the colon, cecum, and stomach but not small intestine in iNOS−/−mice compared with TNF-α-injected wild-type mice. Injection of wild-type mice with 25 μg/kg TNF-α further enhanced VCAM-1 expression by approximately twofold compared with wild-type mice injected with 10 μg/kg TNF-α; however, VCAM-1 expression was not further enhanced in any gastrointestinal organ system in iNOS−/− mice. In a second series of experiments, we found that continuous inhibition of iNOS using oral administration of N G-iminoethyl-l-lysine did not alter the enhanced levels of VCAM-1 expression in the colon nor did it alter the severity of colonic inflammation in SCID mice reconstituted with CD4+, CD45RBhigh T cells. We conclude that iNOS may regulate VCAM-1 expression in acute inflammation; however, this effect is modest and tissue specific and occurs only when VCAM-1 expression is submaximal. iNOS does not appear to modulate VCAM-1 expression in an immune model of chronic colitis.

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