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7 results on '"Marafini I"'

1. Knockdown of Smad7 With a Specific Antisense Oligonucleotide Attenuates Colitis and Colitis-Driven Colonic Fibrosis in Mice.

Author

Izzo R, Bevivino G, De Simone V, Sedda S, Monteleone I, Marafini I, Di Giovangiulio M, Rizzo A, Franzè E, Colantoni A, Ortenzi A, and Monteleone G

Subjects
Animals, Colitis pathology, Collagen Type I analysis, Colon pathology, Crohn Disease therapy, Disease Models, Animal, Down-Regulation, Female, Fibrosis, Gene Knockdown Techniques, Mice, Mice, Inbred BALB C, Oligonucleotides pharmacology, Signal Transduction, Smad3 Protein metabolism, Trinitrobenzenesulfonic Acid, Colitis genetics, Oligonucleotides, Antisense pharmacology, Smad7 Protein genetics, Transforming Growth Factor beta1 metabolism
Abstract

Background: In Crohn's disease (CD), the pathogenic immune response is associated with high Smad7, an inhibitor of TGF-β1 signaling. Smad7 knockdown with Mongersen, a specific antisense oligonucleotide-containing compound, restores TGF-β1 activity leading to inhibition of inflammatory signals and associates with clinical benefit in CD patients. As TGF-β1 is pro-fibrogenic, it remains unclear whether Mongersen-induced Smad7 inhibition increases the risk of intestinal fibrosis. We assessed the impact of Smad7 inhibition on the course of colitis-driven intestinal fibrosis in mice., Methods: BALB/c mice were rectally treated with increasing doses of trinitrobenzene sulfonic acid (TNBS) for 8 or 12 weeks. The effect of oral Smad7 antisense or control oligonucleotide, administered to mice starting from week 5 or week 8, respectively, on mucosal inflammation and colitis-associated colonic fibrosis was assessed. Mucosal samples were analyzed for Smad7 by immunoblotting and immunohistochemistry, TGF-β1 by enzyme-linked immunosorbent assay, and collagen by immunohistochemistry., Results: TNBS-induced chronic colitis was associated with colonic deposition of collagen I and fibrosis, which were evident at week 8 and became more pronounced at week 12. TNBS treatment enhanced Smad7 in both colonic epithelial and lamina propria mononuclear cells. Colitic mice treated with Smad7 antisense oligonucleotide exhibited reduced signs of colitis, less collagen deposition, and diminished fibrosis. These findings were associated with diminished synthesis of TGF-β1 and reduced p-Smad3 protein expression., Conclusion: Attenuation of colitis with Smad7 antisense oligonucleotide limits development of colonic fibrosis.

Published
2018
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2. Inhibiting Oxidative Phosphorylation In Vivo Restrains Th17 Effector Responses and Ameliorates Murine Colitis.

Author

Franchi L, Monteleone I, Hao LY, Spahr MA, Zhao W, Liu X, Demock K, Kulkarni A, Lesch CA, Sanchez B, Carter L, Marafini I, Hu X, Mashadova O, Yuan M, Asara JM, Singh H, Lyssiotis CA, Monteleone G, Opipari AW, and Glick GD

Subjects
Animals, Cell Separation, Disease Models, Animal, Gene Expression Profiling, Humans, Mice, Mice, Inbred C57BL, Oligonucleotide Array Sequence Analysis, Real-Time Polymerase Chain Reaction, Transcriptome, Cell Differentiation immunology, Colitis immunology, Lymphocyte Activation immunology, Oxidative Phosphorylation, Th17 Cells immunology
Abstract

Integration of signaling and metabolic pathways enables and sustains lymphocyte function. Whereas metabolic changes occurring during T cell activation are well characterized, the metabolic demands of differentiated T lymphocytes are largely unexplored. In this study, we defined the bioenergetics of Th17 effector cells generated in vivo. These cells depend on oxidative phosphorylation (OXPHOS) for energy and cytokine production. Mechanistically, the essential role of OXPHOS in Th17 cells results from their limited capacity to increase glycolysis in response to metabolic stresses. This metabolic program is observed in mouse and human Th17 cells, including those isolated from Crohn disease patients, and it is linked to disease, as inhibiting OXPHOS reduces the severity of murine colitis and psoriasis. These studies highlight the importance of analyzing metabolism in effector lymphocytes within in vivo inflammatory contexts and suggest a therapeutic role for manipulating OXPHOS in Th17-driven diseases., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Published
2017
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3. Sodium chloride-enriched Diet Enhanced Inflammatory Cytokine Production and Exacerbated Experimental Colitis in Mice.

Author

Monteleone I, Marafini I, Dinallo V, Di Fusco D, Troncone E, Zorzi F, Laudisi F, and Monteleone G

Subjects
Animals, Disease Models, Animal, Enzyme Inhibitors pharmacology, Interleukin-17 analysis, Mice, Protective Agents pharmacology, Receptors, Interleukin analysis, Statistics as Topic, Treatment Outcome, Tumor Necrosis Factor-alpha analysis, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors, Colitis etiology, Colitis immunology, Colitis metabolism, Colitis prevention & control, Imidazoles pharmacology, Intestinal Mucosa drug effects, Intestinal Mucosa immunology, Intestinal Mucosa pathology, Pyridines pharmacology, Sodium Chloride, Dietary administration & dosage, Sodium Chloride, Dietary adverse effects, Sodium Chloride, Dietary metabolism
Abstract

Background and Aim: Environmental factors are supposed to play a decisive role in the pathogenesis of inflammatory bowel diseases [IBDs]. Increased dietary salt intake has been linked with the development of autoimmune diseases, but the impact of a salt-enriched diet on the course of IBD remains unknown. In this study, we examined whether high salt intake alters mucosal cytokine production and exacerbates colitis., Methods: Normal intestinal lamina propria mononuclear cells [LPMCs] were activated with anti-CD3/CD28 in the presence or absence of increasing concentrations of sodium chloride [NaCl] and/or SB202190, a specific inhibitor of p38/MAP Kinase. For in vivo experiments, a high dose of NaCl was administered to mice 15 days before induction of trinitrobenzene-sulfonic acid [TNBS]-colitis or dextran sulfate sodium [DSS]-colitis. In parallel, mice were given SB202190 before induction of TNBS-colitis. Transcription factors and effector cytokines were evaluated by flow-cytometry and real-time PCR., Results: IL-17A, IL-23R, TNF-α, and Ror-γT were significantly increased in human LPMCs following NaCl exposure, while there was no significant change in IFN-γ, T-bet or Foxp3. Pharmacologic inhibition of p38/MAPK abrogated the NaCl-inducing effect on LPMC-derived cytokines. Mice receiving the high-salt diet developed a more severe colitis than control mice, and this effect was preventable by SB202190., Conclusions: Our data indicated that exposure of intestinal mononuclear cells to a high-NaCl diet enhanced effector cytokine production and contributed to the exacerbation of experimental colitis in mice., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Published
2017
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4. Interleukin-34 induces Cc-chemokine ligand 20 in gut epithelial cells

Author

Angela Ortenzi, Piero Rossi, Roberta Izzo, Veronica De Simone, Alfredo Colantoni, Ivan Monteleone, Pierpaolo Sileri, Eleonora Franzè, Giovanni Monteleone, Francesco Pallone, Giuseppe S. Sica, Francesca Crescenzi, Flavio Caprioli, Irene Marafini, Franze, E, Marafini, I, De Simone, V, Monteleone, I, Caprioli, F, Colantoni, A, Ortenzi, A, Crescenzi, F, Izzo, R, Sica, G, Sileri, P, Rossi, P, Pallone, F, and Monteleone, G

Subjects
0301 basic medicine, Male, Chemokine, colitis, medicine.medical_treatment, Blotting, Western, cytokines, chemokines, intestinal epithelium, Inflammatory bowel disease, Medicine (all), Enzyme-Linked Immunosorbent Assay, Receptor, Macrophage Colony-Stimulating Factor, Real-Time Polymerase Chain Reaction, Sensitivity and Specificity, 03 medical and health sciences, Intestinal mucosa, Crohn Disease, medicine, Humans, Intestinal Mucosa, Cells, Cultured, Settore MED/12 - Gastroenterologia, Chemokine CCL20, biology, Interleukins, Biopsy, Needle, Gastroenterology, Interleukin, Epithelial Cells, General Medicine, Colonoscopy, Beta Chemokine, Intestinal epithelium, Molecular biology, Immunohistochemistry, digestive system diseases, Up-Regulation, CCL20, 030104 developmental biology, Cytokine, biology.protein, Interleukin 34, Colitis, Ulcerative, Female, Biomarkers
Abstract

Background and Aim: Production of chemokines by intestinal epithelial cells is a key step in the amplification of the destructive immune-inflammatory response in patients with inflammatory bowel diseases [IBD]. In this study, we examined whether intestinal epithelial cells express macrophage colony-stimulating factor receptor 1 [M-CSFR-1], the functional receptor of interleukin-34 [IL-34], a cytokine that is over-produced in IBD and supposed to sustain inflammatory pathways. Methods: M-CSFR-1 expression was evaluated in intestinal samples of IBD patients, controls, and colon epithelial cell lines by real-time polymerase chain reaction [PCR], immunohistochemistry, and western blotting. DLD-1 cells were stimulated with IL-34 in the presence or absence of MAP kinase inhibitors, chemokine induction was assessed by real-time PCR and enzyme-linked immunosorbent assay [ELISA], and mitogen-activated protein (MAP) kinase activation was monitored by western blotting. The effect of a neutralising IL-34 antibody on CC chemokine ligand (CCL) 20 synthesis was tested in ex vivo organ cultures of IBD mucosal explants. Results: Enhanced expression of M-CSFR-1 RNA transcripts was seen in inflamed mucosa of IBD patients as compared with controls. Immunohistochemical analysis confirmed up-regulation of M-CSFR-1 in IBD and showed that both epithelial and lamina propria mononuclear cells expressed this receptor. Stimulation of DLD-1 with IL-34 increased CCL20 production through an ERK1/2-dependent mechanism. Consistently, treatment of IBD explants with anti-IL-34 reduced CCL20 production. Conclusions: These data show that intestinal epithelial cells are a target of IL-34 and suggest that this cytokine contributes to mediating the cross-talk between epithelial cells and immune cells in IBD.

Published
2016

5. Smad7 Knockdown Restores Aryl Hydrocarbon Receptor-mediated Protective Signals in the Gut

Author

Giuseppe S. Sica, Irene Marafini, Francesca Zorzi, Vincenzo Dinallo, Angela Rizzo, Ivan Monteleone, Pierpaolo Sileri, Giovanni Monteleone, Davide Di Fusco, Monteleone, I, Marafini, I, Zorzi, F, Di Fusco, D, Dinallo, V, Rizzo, A, Sileri, P, Sica, G, and Monteleone, G

Subjects
Crohn’s disease, 0301 basic medicine, T-Lymphocytes, Inbred C57BL, Transgenic, Ficz, Interleukin 22, Mice, Crohn Disease, TGF-β, colitis, inflammation, intestine, Adult, Aged, Animals, Basic Helix-Loop-Helix Transcription Factors, Carbazoles, Case-Control Studies, Colitis, Female, Gene Knockdown Techniques, Humans, Ileum, Interleukins, Intestinal Mucosa, Leukocytes, Mononuclear, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Receptors, Aryl Hydrocarbon, Smad7 Protein, Transforming Growth Factor beta1, Receptors, Leukocytes, Receptor, Settore MED/12 - Gastroenterologia, Gene knockdown, integumentary system, Crohn's disease, Inflammation, Intestine, Gastroenterology, Interleukin, General Medicine, Aryl Hydrocarbon, medicine.symptom, medicine.medical_specialty, Mononuclear, Biology, 03 medical and health sciences, Immune system, Internal medicine, medicine, Transforming growth factor beta, Aryl hydrocarbon receptor, Molecular biology, Settore MED/18 - Chirurgia Generale, 030104 developmental biology, Endocrinology, biology.protein
Abstract

Background and Aim: In Crohn’s disease [CD], the pathological process is driven by an excessive immune response that is poorly counterbalanced by regulatory mechanisms. One such a mechanism involves aryl hydrocarbon receptor [AhR], a transcription factor that delivers protective signals in the gut. Expression of AhR is reduced in CD lamina propria mononuclear cells [LPMC] even though factors accounting for such a defect remain unknown. Since CD LPMC express elevated levels of Smad7, an inhibitor of transforming growth factor beta 1 [TGF-β1] activity, and TGF-β1 regulates AhR in other systems, we examined the link between AhR and Smad7 in the gut. Methods: AhR and interleukin [IL]-22 were evaluated in normal LPMC stimulated with TGF-β1 and 6-formylindolo[3,2-b]carbazole [Ficz], an activator of AhR, and in CD LPMC incubated with a Smad7 antisense oligonucleotide and then stimulated with Ficz and TGF-β1. AhR and IL-22 expression was evaluated in LPMC of Smad7-transgenic mice. Finally, we evaluated the protective effect of Ficz on colitis in RAG1 mice injected with naive or Smad7-overexpressing T cells. Results: In normal LPMC, TGF-β1 induced AhR and this event was associated with increased production of IL-22 following stimulation with Ficz. Treatment of CD LPMC with Smad7 antisense oligonucleotide enabled TGF-β1 to enhance AhR expression. Consistently, AhR expression and Ficz-induced IL-22 production were markedly reduced in T cells of Smad7-transgenic mice. In RAG1 mice, Ficz ameliorated colitis induced by wild type T cells but did not affect colitis induced by transfer of Smad7-overexpressing T cells. Conclusions: The inverse correlation between Smad7 and AhR expression helps to propagate inflammatory signals in the gut.

Published
2015

6. Interleukin-34 sustains inflammatory pathways in the gut

Author

Angela Ortenzi, Flavio Caprioli, Irene Marafini, Giuseppe S. Sica, Pamela Mancia, Francesco Pallone, Giovanni Monteleone, Alfredo Colantoni, Maria Laura Cupi, Ivan Monteleone, Pierpaolo Sileri, Federica Laudisi, Eleonora Franzè, Franze, E, Monteleone, I, Cupi, Ml, Mancia, P, Caprioli, F, Marafini, I, Colantoni, A, Ortenzi, A, Laudisi, F, Sica, G, Sileri, P, Pallone, F, and Monteleone, G

Subjects
Chemokine, Colitis, Ulcerative, Crohn Disease, Enteroendocrine Cells, Humans, Inflammation, Interleukins, MAP Kinase Signaling System, Macrophages, Tumor Necrosis Factor-alpha, medicine.medical_treatment, Ulcerative, Inflammatory bowel disease, medicine, Settore MED/12 - Gastroenterologia, Lamina propria, biology, business.industry, Monocyte, Interleukin, General Medicine, medicine.disease, Colitis, digestive system diseases, Settore MED/18 - Chirurgia Generale, medicine.anatomical_structure, Cytokine, Immunology, Interleukin 34, biology.protein, Tumor necrosis factor alpha, business
Abstract

IBD (inflammatory bowel disease)-related tissue damage occurs in areas which are massively infiltrated with monocytes/macrophages. These cells respond to inflammatory stimuli with enhanced production of cytokines/chemokines. In the present study, we analysed the expression and role of IL (interleukin)-34, a regulator of monocyte/macrophage differentiation, survival and function, in IBD. A significant increase in IL-34 mRNA and protein expression was seen in inflamed mucosa of patients with CD (Crohn's disease) and patients with UC (ulcerative colitis) compared with the uninvolved areas of the same patients and normal controls. IL-34 was up-regulated in LPMCs (lamina propria mononuclear cells) isolated from normal colon by TNF-α (tumour necrosis factor α) and TLR (Toll-like receptor) ligands and was down-regulated in intestinal biopsies and LPMCs of IBD patients upon treatment with infliximab. Treatment of normal LPMCs with IL-34 increased TNF-α expression in an ERK1/2 (extracellular-signal-regulated kinase 1/2)-dependent fashion and neutralization of IL-34 in IBD mucosal explants reduced TNF-α and IL-6 synthesis. In conclusion, our results indicate that IL-34 is up-regulated in IBD and suggest a role for this cytokine in sustaining the inflammatory responses in this disease.

Published
2015

7. Defective expression of SIRT1 contributes to sustain inflammatory pathways in the gut

Author

Carmine Stolfi, Francesca Zorzi, Giuseppe S. Sica, Livia Biancone, Rosario Caruso, Francesco Pallone, Alfredo Colantoni, Massimiliano Sarra, Giovanni Monteleone, Eleonora Franzè, Thomas T. MacDonald, Flavio Caprioli, Irene Marafini, Silvia Sedda, Ivan Monteleone, Pierpaolo Sileri, Caruso, R, Marafini, I, Franzè, E, Stolfi, C, Zorzi, F, Monteleone, I, Caprioli, F, Colantoni, A, Sarra, M, Sedda, S, Biancone, L, Sileri, P, Sica, G, Macdonald, T, Pallone, F, and Monteleone, G

Subjects
Adult, Male, Immunology, Biology, Inflammatory bowel disease, Gene Expression Regulation, Enzymologic, Interferon-gamma, Mice, Immune system, Adjuvants, Immunologic, Sirtuin 1, Interferon, medicine, Immunology and Allergy, Animals, Humans, Colitis, Aged, Regulation of gene expression, Aged, 80 and over, Lamina propria, Settore MED/12 - Gastroenterologia, Tumor Necrosis Factor-alpha, Interleukins, Anti-Inflammatory Agents, Non-Steroidal, Oxazolone, Interleukin, Antibodies, Monoclonal, Middle Aged, medicine.disease, Inflammatory Bowel Diseases, Infliximab, Intestines, medicine.anatomical_structure, Trinitrobenzenesulfonic Acid, Tumor necrosis factor alpha, Female, hormones, hormone substitutes, and hormone antagonists, medicine.drug
Abstract

In inflammatory bowel disease (IBD), tissue damage is driven by an excessive immune response, poorly controlled by counter-regulatory mechanisms. SIRT1, a class III NAD+-dependent deacetylase, regulates negatively the expression of various proteins involved in the control of immune-inflammatory pathways, such as Stat3, Smad7, and NF-κB. Here we examined the expression, regulation, and function of SIRT1 in IBD. SIRT1 RNA and protein expression was less pronounced in whole biopsies and lamina propria mononuclear cells (LPMCs) of IBD patients in comparison with normal controls. SIRT1 expression was downregulated in control LPMC by tumor necrosis factor (TNF)-α and interleukin (IL)-21, and upregulated in IBD LPMC by neutralizing TNF-α and IL-21antibodies. Consistently, SIRT1 expression was increased in mucosal samples taken from IBD patients successfully treated with Infliximab. Treatment of IBD LPMC with Cay10591, a specific SIRT1 activator, reduced NF-κB activation and inhibited inflammatory cytokine synthesis, whereas Ex527, an inhibitor of SIRT1, increased interferon (IFN)-γ in control LPMC. SIRT1 was also reduced in mice with colitis induced by 2,4,6-trinitrobenzenesulphonic acid or oxazolone. Cay10591 prevented and cured experimental colitis whereas Ex527 exacerbated disease by modulating T cell-derived cytokine response. Data indicate that SIRT1 is downregulated in IBD patients and colitic mice and suggest that SIRT1 activation can help attenuate inflammatory signals in the gut.Mucosal Immunology advance online publication, 21 May 2014; doi:10.1038/mi.2014.35.

Published
2013

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