Phosphatase Shp2 exacerbates intestinal inflammation by disrupting macrophage responsiveness to interleukin-10

Inflammatory cytokines produced by activated macrophages largely contribute to the pathological signs of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is the predominant anti-inflammatory cytokine in the intestine, and its therapeutic efficacy for IBD has been clinically tested. Nevertheless, how the function of IL-10 is regulated in the intestinal microenvironment remains unknown, which largely hinders the further development of IL-10–based therapeutic strategies. Here, we found that the expression of phosphatase Shp2 was increased in colonic macrophages and blood monocytes from IBD patients compared with those from healthy controls. Shp2 deficiency in macrophages protects mice from colitis and colitis-driven colon cancer. Mechanistically, Shp2 disrupts IL-10–STAT3 signaling and its dependent anti-inflammatory response in human and mouse macrophages. Furthermore, a Shp2-inducing role of TNF-α is unveiled in our study. Collectively, our work identifies Shp2 as a detrimental factor for intestinal immune homeostasis and hopefully will be helpful in the future exploitation of IL-10 immunotherapy for IBD.

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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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Yoghurt Consumption Regulates the Immune Cells Implicated in Acute Intestinal Inflammation and Prevents the Recurrence of the Inflammatory Process in a Mouse Model

Journal of Food Protection ◽

10.4315/0362-028x.jfp-10-375 ◽

2011 ◽

Vol 74 (5) ◽

pp. 801-811 ◽

Cited By ~ 32

Author(s):

SILVINA CHAVES ◽

GABRIELA PERDIGON ◽

ALEJANDRA de MORENO de LeBLANC

Keyword(s):

Inflammatory Bowel Disease ◽

T Cell ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Disease Model ◽

Interleukin 10 ◽

Trinitrobenzene Sulfonic Acid ◽

Industrialized Countries ◽

Inflammatory Bowel ◽

Anti Inflammatory

Crohn's disease and ulcerative colitis, two forms of inflammatory bowel disease, are important problems in industrialized countries. The complete etiology of these two diseases is still unknown but likely involves genetic, environmental, and immunological factors. The aim of the present work was to determine whether the anti-inflammatory effects reported for yoghurt in acute trinitrobenzene sulfonic acid–induced intestinal inflammation in mice also could prevent or attenuate the recurrent intestinal inflammation, thus maintaining remission. The innate response also was evaluated through participation of Toll-like receptors (TLRs) and the analysis of T-cell populations to determine the effects of yoghurt in an acute inflammatory bowel disease model. Yoghurt exerted a beneficial effect on acute intestinal inflammation by regulating T-cell expansion and modulating the expression of TLRs, with decrease of TLR4+ and increase of TLR9+ cells. The anti-inflammatory effect of yoghurt also was demonstrated in a recurrent inflammation model. Yoghurt administration during the remission phase prevented the recurrence of inflammation without producing undesirable side effects. The yoghurt effect may be mediated by increased interleukin 10 production and changes in intestinal microbiota.

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Bidens pilosa (Black Jack) Standardized Extract Ameliorates Acute TNBS-induced Intestinal Inflammation in Rats

Planta Medica ◽

10.1055/a-1089-8342 ◽

2020 ◽

Vol 86 (05) ◽

pp. 319-330

Author(s):

Ana E.V. Quaglio ◽

Vinicius M. Cruz ◽

Luiz D. Almeida-Junior ◽

Celso A.R.A. Costa ◽

Luiz C. Di Stasi

Keyword(s):

Intestinal Inflammation ◽

Gastric Ulcers ◽

Bidens Pilosa ◽

Tem Analysis ◽

Beneficial Effects ◽

Transmission Electron ◽

Tnf Α ◽

Inflammatory Bowel ◽

Anti Inflammatory ◽

Α Level

Abstract Bidens pilosa is an herb popularly used to treat inflammation, hemorrhoids, fever, and gastric ulcers with reported pharmacological activities and chemical composition that sustain its selection as a potential intestinal anti-inflammatory product. Based on this, we examined the effects of a B. pilosa fatty acid-standardized supercritical preparation on the intestinal inflammatory process induced by trinitrobenzenesulphonic acid in rats, using either preventative or curative treatments. We also investigated the safety of plant extract by acute and sub-chronic toxicological analysis. The intestinal anti-inflammatory activity was related to modulation of the immune response, increasing IL-10 production and reducing IL-1β, IL-6, and TNF-α level, the oxidative stress, and the MUC production in the inflamed colon. Optic, scanning, and transmission electron microscopy (TEM) analysis supported the beneficial effects promoted by B. pilosa, which were closely related to downregulation of heparanase, Hsp70, Mapk 3, and NF-κB signaling and with the presence of long-chain fatty acids in extract. Our data suggest that B. pilosa supercritical preparation is a chemically standardized preparation potentially useful as complementary intestinal anti-inflammatory agent to treat inflammatory bowel disease.

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P009 The innate cytokines IL-1α and TNF-α induce the expression of Oncostatin M and its type II receptor in human colonic subepithelial myofibroblasts

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.138 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S134-S134

Author(s):

E Filidou ◽

G Kokkotis ◽

G Tarapatzi ◽

M Boulkou ◽

K Arvanitidis ◽

...

Keyword(s):

Intestinal Inflammation ◽

Fold Increase ◽

Oncostatin M ◽

Type Ii ◽

Basal Expression ◽

Tnf Α ◽

Inflammatory Bowel ◽

Colonic Biopsies ◽

Pro Inflammatory Cytokines

Abstract Background Oncostatin M (OSM), a cytokine of the IL-6 family, has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Specifically, OSM and its receptor, OSMR, are elevated in inflamed colonic regions of IBD patients; in addition, high OSM expression at baseline has been associated with failure to respond to anti-TNF. OSMR expression localised in stromal cells of the intestinal lamina propria. Our aim was to investigate the expression of OSM and its receptors subunits, OSMR, LIFR and gp-130 in primary subepithelial myofibroblasts (SEMFs) and test whether this expression is regulated by the innate cytokines, IL-1α and TNF-α. Methods Primary SEMFs were isolated from endoscopically-obtained colonic biopsies from healthy controls, set to culture and stimulated with 5ng/ml IL-1α and/or 50ng/ml TNF-α for 6 h. Total RNA was extracted and the mRNA transcripts for OSM, OSMR, LIFR and gp-130 were measured by reverse transcription-quantitative (RT-q) PCR. Results Unstimulated SEMFs had a basal expression of both OSM and its receptors subunits. IL-1α or TNF-α stimulations did not alter LIFR expression, but they induced a statistically significant upregulation of OSM, OSMR and gp-130. Specifically, the expression of OSM in SEMFs was significantly upregulated after stimulation with IL-1α alone or in combination with TNF-α (IL-1α: 11.48-fold increase, 8.29–26.05; IL-1α+TNF-α: 13.42-fold, 11.32–17.16; p < 0.0001). Regarding the OSMR and gp-130 subunits [which form the type II receptor of OSM], OSMR mRNA was induced by TNF-α alone or in combination with IL-1α (TNF-α: 1.75-fold, 1.27–2.02, p < 0.01; IL-1α+TNF-α: 2.06-fold, 1.83–2.34, p < 0.0001), whereas gp-130 mRNA expression was increased under all stimulatory conditions (IL-1α: 1.94-fold, 1.46–2.07; TNF-α: 1.81-fold, 1.46–2.25; IL-1α+TNF-α: 1.59-fold, 1.31–2.51; p < 0.01 for all comparisons). Conclusion Our results show that OSM and OSMR are expressed on primary human SEMFs and that they are upregulated under stimulation with innate pro-inflammatory cytokines. These data further support a potential role of this system of inflammatory mediators in the pathogenesis of intestinal inflammation.

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Protective and anti-inflammatory role of REG1A in inflammatory bowel disease induced by JAK/STAT3 signaling axis

International Immunopharmacology ◽

10.1016/j.intimp.2020.107304 ◽

2021 ◽

Vol 92 ◽

pp. 107304

Author(s):

Hongli Mao ◽

Jinlin Jia ◽

Jinxiu Sheng ◽

Shanfeng Zhang ◽

Kaida Huang ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Stat3 Signaling ◽

Signaling Axis ◽

Inflammatory Bowel ◽

Anti Inflammatory

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Dual Role of Interleukin-10 in Murine NZB/W F1 Lupus

International Journal of Molecular Sciences ◽

10.3390/ijms22031347 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1347

Author(s):

Anaïs Amend ◽

Natalie Wickli ◽

Anna-Lena Schäfer ◽

Dalina T. L. Sprenger ◽

Rudolf A. Manz ◽

...

Keyword(s):

B Cell ◽

Disease Model ◽

Interleukin 10 ◽

Immune Functions ◽

Murine Lupus ◽

Anti Inflammatory ◽

In Vivo Effects

As a key anti-inflammatory cytokine, IL-10 is crucial in preventing inflammatory and autoimmune diseases. However, in human and murine lupus, its role remains controversial. Our aim was to understand regulation and immunologic effects of IL-10 on different immune functions in the setting of lupus. This was explored in lupus-prone NZB/W F1 mice in vitro and vivo to understand IL-10 effects on individual immune cells as well as in the complex in vivo setting. We found pleiotropic IL-10 expression that largely increased with progressing lupus, while IL-10 receptor (IL-10R) levels remained relatively stable. In vitro experiments revealed pro- and anti-inflammatory IL-10 effects. Particularly, IL-10 decreased pro-inflammatory cytokines and slowed B cell proliferation, thereby triggering plasma cell differentiation. The frequent co-expression of ICOS, IL-21 and cMAF suggests that IL-10-producing CD4 T cells are important B cell helpers in this context. In vitro and in vivo effects of IL-10 were not fully concordant. In vivo IL-10R blockade slightly accelerated clinical lupus manifestations and immune dysregulation. Altogether, our side-by-side in vitro and in vivo comparison of the influence of IL-10 on different aspects of immunity shows that IL-10 has dual effects. Our results further reveal that the overall outcome may depend on the interplay of different factors such as target cell, inflammatory and stimulatory microenvironment, disease model and state. A comprehensive understanding of such influences is important to exploit IL-10 as a therapeutic target.

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N-Acetylcysteine (NAC): Impacts on Human Health

Antioxidants ◽

10.3390/antiox10060967 ◽

2021 ◽

Vol 10 (6) ◽

pp. 967

Author(s):

Micaely Cristina dos Santos Tenório ◽

Nayara Gomes Graciliano ◽

Fabiana Andréa Moura ◽

Alane Cabral Menezes de Oliveira ◽

Marília Oliveira Fonseca Goulart

Keyword(s):

Human Health ◽

Therapeutic Potential ◽

Experimental Studies ◽

Primary Role ◽

Necrosis Factor Alpha ◽

Biochemical Basis ◽

Tnf Α ◽

Factor Alpha ◽

Anti Inflammatory

N-acetylcysteine (NAC) is a medicine widely used to treat paracetamol overdose and as a mucolytic compound. It has a well-established safety profile, and its toxicity is uncommon and dependent on the route of administration and high dosages. Its remarkable antioxidant and anti-inflammatory capacity is the biochemical basis used to treat several diseases related to oxidative stress and inflammation. The primary role of NAC as an antioxidant stems from its ability to increase the intracellular concentration of glutathione (GSH), which is the most crucial biothiol responsible for cellular redox imbalance. As an anti-inflammatory compound, NAC can reduce levels of tumor necrosis factor-alpha (TNF-α) and interleukins (IL-6 and IL-1β) by suppressing the activity of nuclear factor kappa B (NF-κB). Despite NAC’s relevant therapeutic potential, in several experimental studies, its effectiveness in clinical trials, addressing different pathological conditions, is still limited. Thus, the purpose of this chapter is to provide an overview of the medicinal effects and applications of NAC to human health based on current therapeutic evidence.

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Obesity and inflammatory bowel disease

Gastroenterologie a hepatologie ◽

10.48095/ccgh202120 ◽

2021 ◽

Vol 75 (1) ◽

pp. 20-28

Author(s):

Vladimír Teplan ◽

Milan Lukáš

Keyword(s):

Inflammatory Bowel Disease ◽

Adipose Tissue ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Perioperative Complications ◽

Overweight And Obesity ◽

Special Role ◽

Low Concentrations ◽

Inflammatory Bowel

The incidence and prevalence of overweight and obesity has dramatically increased in the last decades and is generally considered to be global pandemics. The incidence of inflammatory bowel disease (IBD) is rising parallel with overweight and obesity. Contrary to a conventional believe, about 15–40% patients with IBD are obese, which can contribute to the development and course of IBD, especially in Crohn’s disease. Although the findings of some cohort studies are still conflicting, recent results indicate a special role of visceral adipose tissue and particularly mesenteric adipose tissue known as creeping fat, leading to intestinal inflammation. The involvement of altered adipocyte function and deregulated production of adipokines such as leptin and adiponectin has been suggested in the pathogenesis of IBD. The emerging role of Western diet and microbiota can also open new possibilities in IBD management. The effect of obesity on the IBD-related therapy remains to be studied. The finding that obesity results in suboptimal response to the therapy, potentially promoting rapid clearance of biologic agents and thus leading to their low concentrations, has a great importance. Obesity also makes IBD colorectal surgery technically challenging and might increase a risk of perioperative complications.

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Impact of Cigarette Smoking on Serum Pro- and Anti-Inflammatory Cytokines and Growth Factors

American Journal of Men s Health ◽

10.1177/1557988315601724 ◽

2015 ◽

Vol 11 (4) ◽

pp. 1169-1173 ◽

Cited By ~ 10

Author(s):

Mahdi Hasanzadeh Daloee ◽

Amir Avan ◽

Seyed Reza Mirhafez ◽

Elahe Kavousi ◽

Mehdi Hasanian-Mehr ◽

...

Keyword(s):

Growth Factors ◽

Cigarette Smoking ◽

Inflammatory Cytokines ◽

Female Group ◽

Serum Concentrations ◽

Medical Sciences ◽

Cigarette Smokers ◽

Tnf Α ◽

Anti Inflammatory

Inflammation plays a key role in the initiation, progression, and clinical manifestation of atherosclerosis. Cigarette smoking is a risk factor for atherosclerosis and cardiovascular disease. The aim of the current study was to investigate the serum concentrations of 12 cytokines and growth factors (EGF, INF-γ, IL-1α/-1β/-2/-4/-6/-8/-10, MCP-1, TNF-α, and VEGF) in an Iranian population, including 192 smokers, comparing these values with concentrations in nonsmokers. One hundred and ninety-two cases were enrolled from the Mashhad University of Medical Sciences. Of these cases, 82 were cigarette smokers and 110 were nonsmokers. Sex and age were matched for the two groups. The serum concentration of 12 cytokines and growth factors were determined using EV-3513-cytokine-biochip arrays, by competitive chemiluminescence immunoassays. The level of serum MCP-1 was significantly ( p < .001) lower in the female group of cigarette smokers (mean = 88.1 dL/ng), compared with nonsmokers (mean = 155.6 dL/ng). There were no significant differences for the other cytokines and growth factors between the groups. Our finding demonstrate the association of MCP-1 with cigarette smoking, supporting further studies in larger population on evaluating the role of cigarette smoking on pro-/anti-inflammatory cytokines.

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Thymus leukemia antigen controls intraepithelial lymphocyte function and inflammatory bowel disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0808242105 ◽

2008 ◽

Vol 105 (46) ◽

pp. 17931-17936 ◽

Cited By ~ 38

Author(s):

Danyvid Olivares-Villagómez ◽

Yanice V. Mendez-Fernandez ◽

Vrajesh V. Parekh ◽

Saif Lalani ◽

Tiffaney L. Vincent ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Genetic Model ◽

Critical Role ◽

Intraepithelial Lymphocytes ◽

Lymphocyte Function ◽

Intestinal Epithelial ◽

Inflammatory Bowel

Intestinal intraepithelial lymphocytes (IEL) bear a partially activated phenotype that permits them to rapidly respond to antigenic insults. However, this phenotype also implies that IEL must be highly controlled to prevent misdirected immune reactions. It has been suggested that IEL are regulated through the interaction of the CD8αα homodimer with the thymus leukemia (TL) antigen expressed by intestinal epithelial cells. We have generated and characterized mice genetically-deficient in TL expression. Our findings show that TL expression has a critical role in maintaining IEL effector functions. Also, TL deficiency accelerated colitis in a genetic model of inflammatory bowel disease. These findings reveal an important regulatory role of TL in controlling IEL function and intestinal inflammation.

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