• Humans
• Crohn Disease/epidemiology
• Crohn Disease/microbiology
• Crohn Disease/pathology
• Escherichia coli
• Escherichia coli Infections/epidemiology
• Escherichia coli Infections/microbiology
• Escherichia coli Infections/pathology
• Bacterial Adhesion
• Intestinal Mucosa/microbiology
• Intestinal Mucosa/pathology

• Cytotoxin-associated antigen A oncoprotein
• Gut microbiota
• Helicobacter pylori
• Helicobacter pylori neutrophil-activating protein
• Immunological modulation
• Inflammatory bowel disease
• NLR family pyrin domain containing 3 inflammasome

• Humans
• Helicobacter pylori
• Helicobacter Infections/complications
• Immunity, Innate
• Inflammatory Bowel Diseases
• Stomach

• IL-13
• JAK
• inflammatory bowel disease
• nociception
• p38 MAPK

A certain number of patients with ulcerative colitis (UC) are refractory to anti-TNF-α antibodies; biomarkers are thus needed to predict treatment efficacy. This study aimed to evaluate whether serum biomarkers that were reported to be associated with UC or anti-TNF-α antibody could predict the response to golimumab, a human anti-TNF-α monoclonal antibody, in bio-naïve patients with UC. We prospectively enrolled 23 consecutive patients with UC who were treated with golimumab. Serum samples were collected before the first golimumab dose. Eleven molecules were measured by electrochemiluminescence (ECL) or enzyme-linked immunosorbent assay (ELISA) and their association with efficacy after 10 weeks of golimumab treatment. Among the serum biomarkers, IL-13 levels were significantly higher in the non-remission group than in the remission group (p = 0.014). IL-15 levels were significantly lower in the non-response group than in the response group (p = 0.04). For clinical remission at week 10, the IL-13 0.20 concentration of pg/mL was associated with a sensitivity and specificity of 82.4% and 83.3%, respectively. Serum IL-13 may be a biomarker to predict golimumab efficacy in biologic-naïve patients with UC, and thus may help to tailor personalized treatment strategies.

The liver is a major metabolic organ and an immunologically complex organ. It produces and uses many substances such as acute phase proteins, cytokines, chemokines, and complementary components to maintain the balance between immunity and tolerance. Interleukins are important immune control cytokines, that are produced by many body cells. In liver injury, interleukins are produced in large amount by various cell types, and act as pro-inflammatory (e.g. interleukin (IL)-6, IL-13, IL-17, and IL-33) as well as anti-inflammatory (e.g. IL-10) functions in hepatic cells. Recently, interleukins are regarded as interesting therapeutic targets for the treatment of liver fibrosis patients. Hepatic cells such as hepatocytes, hepatic stellate cells, and hepatic macrophages are involved to the initiation, perpetuation, and resolution of fibrosis. The understanding of the role of interleukins in such cells provides opportunity for the development of therapeutic target drugs. This paper aims to understand the functional roles of interleukins in hepatic and immune cells when the liver is damaged, and suggests the possibility of interleukins as a new treatment target in liver fibrosis.

• CD4+ T helper cells
• hepatic stellate cells
• hepatocytes
• interleukins
• liver fibrosis
• macrophages

We posit that interleukin-15 (IL-15) is a relevant contributor to MS pathobiology as this cytokine is elevated in the CNS and periphery of patients with MS. We aim to investigate (1) the impact of IL-15 on T lymphocytes from patients with MS and (2) the in vivo role of IL-15 using the experimental autoimmune encephalomyelitis (EAE) mouse model.

We compared the impact of IL-15 on T lymphocytes obtained from untreated patients with MS (relapsing-remitting, secondary progressive, and primary progressive) to cells from age/sex-matched healthy controls (HCs) using multiparametric flow cytometry and in vitro assays. We tested the effects of peripheral IL-15 administration after EAE disease onset in C57BL/6 mice.

IL-15 triggered STAT5 signaling in an elevated proportion of T cells from patients with MS compared with HCs. This cytokine also enhanced the production of key proinflammatory cytokines (interferon γ, granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-17, and tumor necrosis factor) by T cells from both MS and controls, but these effects were more robust for the production of IL-17 and GM-CSF in T-cell subsets from patients with MS. At the peak of EAE disease, the proportion of CD4⁺ and CD8⁺ T cells expressing CD122⁺, the key signaling IL-15 receptor chain, was enriched in the CNS compared with the spleen. Finally, peripheral administration of IL-15 into EAE mice after disease onset significantly aggravated clinical scores and increased the number of inflammatory CNS-infiltrating T cells long term after stopping IL-15 administration.

Our results underscore that IL-15 contributes to the amplification of T-cell inflammatory properties after disease onset in both MS and EAE.

• Claudins
• Inflammatory bowel disease
• Tight junction
• Vitamin D

• Cytokines
• Endoplasmic reticulum stress
• IBD
• Intestinal compartments
• Laser capture microdissection
• Th1
• Th17
• Treg

• Adult
• Aged
• Cytokines/genetics
• Cytokines/metabolism
• Female
• Humans
• Immunohistochemistry
• Inflammatory Bowel Diseases/immunology
• Intestinal Mucosa/immunology
• Laser Capture Microdissection/methods
• Leukocyte Elastase/metabolism
• Male
• Middle Aged
• Th1 Cells/immunology
• Th17 Cells/immunology
• Young Adult

• Th2
• bowel
• canine
• cytokine
• duodenum
• inflammatory

Crohn’s disease and ulcerative colitis are driven by both common and distinct underlying mechanisms of pathobiology. Both diseases, exhibit heterogeneity underscored by the variable clinical responses to therapeutic interventions.

We aimed to identify disease-driving pathways and classify individuals into subpopulations that differ in their pathobiology and response to treatment.

We applied hierarchical clustering of enrichment scores derived from gene set variation analysis of signatures representative of various immunological processes and activated cell types, to a colonic biopsy dataset that included healthy volunteers, Crohn’s disease and ulcerative colitis patients. Patient stratification at baseline or after anti-TNF treatment in clinical responders and non-responders was queried. Signatures with significantly different enrichment scores were identified using a general linear model. Comparisons to healthy controls were made at baseline in all participants and then separately in responders and non-responders. Fifty-nine percent of the signatures were commonly enriched in both conditions at baseline, supporting the notion of a disease continuum within ulcerative colitis and Crohn’s disease. Signatures included T cells, macrophages, neutrophil activation and poly:IC signatures, representing acute inflammation and a complex mix of potential disease-driving biology. Collectively, identification of significantly enriched signatures allowed establishment of an inflammatory bowel disease molecular activity score which uses biopsy transcriptomics as a surrogate marker to accurately track disease severity. This score separated diseased from healthy samples, enabled discrimination of clinical responders and non-responders at baseline with 100% specificity and 78.8% sensitivity, and was validated in an independent data set that showed comparable classification. Comparing responders and non-responders separately at baseline to controls, 43% and 70% of signatures were enriched, respectively, suggesting greater molecular dysregulation in TNF non-responders at baseline. This methodological approach could facilitate better targeted design of clinical studies to test therapeutics, concentrating on patient subsets sharing similar underlying pathobiology, therefore increasing the likelihood of clinical response.

Patients exhibiting similar phenotypical characteristics, diagnosed with the same disease, exhibit variable response to therapeutics. This is a major health care issue, due to the increased patient suffering and the socioeconomical burden that occurs. Crohn’s disease and ulcerative colitis constitute good examples of inflammatory conditions, with sufferers responding differentially to existent therapeutics. Here, we identified disease-driving pathways and classified individuals into subpopulations that differ in their pathobiology and response to treatment. We utilized gene set variation analysis and transcriptomic data from inflammatory bowel disease sufferers to stratify patients at baseline or after anti-TNF treatment in clinical responders and non-responders. We explored gene signatures obtained from the literature, relevant to immune processes, which were significantly enriched in disease compared to healthy controls, as well as before and after treatment. Using these signatures, we established an inflammatory bowel disease molecular activity score, which allowed us to separate clinical responders and non-responders at baseline with high specificity and sensitivity. We validated the proposed approach in an independent data set, demonstrating comparable classification. This methodological approach may lead to better targeted design of clinical studies, allowing the selection of patient sharing similar underlying pathobiology, thus increasing the likelihood of clinical response to treatment.

• Cluster Analysis
• Colon/chemistry
• Colon/metabolism
• Computational Biology/methods
• Drug Monitoring
• Gastrointestinal Agents/therapeutic use
• Gene Expression Profiling
• Humans
• Inflammatory Bowel Diseases/classification
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/genetics
• Inflammatory Bowel Diseases/metabolism
• Infliximab/therapeutic use
• Transcriptome/genetics
• Tumor Necrosis Factor-alpha/antagonists & inhibitors

Inflammatory bowel diseases (IBDs) include colitis ulcerosa and Crohn's disease, besides the rare microscopic colitis. Both diseases show a long-lasting, relapsing-remitting, or even chronic active course with tremendous impact on quality of life. IBDs frequently cause disability, surgical interventions, and high costs; as in other autoimmune diseases, their prevalent occurrence at an early phase of life raises the burden on health care systems. Unfortunately, our understanding of the pathogenesis is still incomplete and treatment therefore largely focuses on suppressing the resulting excessive inflammation. One obstacle for deciphering the causative processes is the scarcity of models that parallel the development of the disease, since intestinal inflammation is mostly induced artificially; moreover, the intestinal epithelium, which strongly contributes to IBD pathogenesis, is difficult to assess. Recently, the development of intestinal epithelial organoids has overcome many of those problems. Here, we give an overview on the current understanding of the pathogenesis of IBDs with reference to the limitations of previous well-established experimental models. We highlight the advantages and detriments of recent organoid-based experimental setups within the IBD field and suggest possible future applications.

• epithelium
• gut
• inflammation
• interleukin-13
• microRNAs
• ulcerative colitis

• MR/K001035/1 Medical Research Council

• Crohn’s disease
• Innate lymphoid cell
• Mucosal-associated invariant T cell
• Natural killer T cell
• Ulcerative colitis

Inflammatory bowel diseases (IBD) are a growing health problem worldwide, severely affecting patients’ life qualities and life expectancies. Therapeutic options, which are rare and focus on symptoms associated with the disease, suffer from increasing numbers of patients refractory to the established strategies. Thus, in order to generate new therapeutic regimens, the detailed understanding of the pathogenic mechanisms causing IBD is necessary. Histamine is an inflammatory mediator associated with IBD. Four histamine receptors are currently known of which the histamine H₄-receptor (H₄R) has been shown to possess a pro-inflammatory function in several experimental models of inflammatory diseases, including dextran sodium sulfate (DSS)-induced colitis in mice. No single model reflects the complexity of human IBD, but each model provides valuable information on specific aspects of IBD pathogenesis. While DSS-induced colitis mostly relies on innate immune mechanisms, trinitrobenzene sulfonic acid (TNBS)-induced colitis rather reflects T-cell mechanisms. Consequently, an observation made in a single model has to be verified in at least one other model. Therefore, in the present study we investigated the effect of genetic blockade of H₄R-signaling in mice subjected to the model of TNBS-induced acute colitis. We analyzed severity and progression of clinical signs of colitis, as well as histopathologic alterations in the colon and local cytokine production. Genetic ablation of H₄R expression worsened clinical signs of acute colitis and histological appearance of colon inflammation after TNBS application. Moreover, TNBS instillation enhanced local synthesis of inflammatory mediators associated with a neutrophilic response, i.e., CXCL1, CXCL2, and interleukin-6. Lastly, also myeloperoxidase concentration, indicative for the presence of neutrophils, was elevated in cola of TNBS-treated mice due to the absence of H₄R expression. Our results indicate an anti-inflammatory role of histamine via H₄R in TNBS-induced acute neutrophilic colitis in mice, thus questioning the strategy of pharmacological H₄R blocked as new therapeutic option for patients suffering from IBD.

• GPCR
• TNBS-induced colitis
• histamine
• inflammation
• mouse models
• receptor

In the recent years, the incidence of inflammatory bowel disease (IBD) has dramatically increased in young subjects, however, the pathogenesis of paediatric IBD is poorly investigated. In this study we aimed to evaluate the cytokine pattern and the phenotype of cytokine producing cells in the intestinal mucosa of paediatric patients affected by Crohn’s disease (CD) or ulcerative colitis (UC) and of non-IBD healthy controls (HC). Cytokine (IL-15, TNF-α, INF-γ) production was analyzed at basal condition and after mitogen stimulation either intracellularly by flow cytometry or in intestinal cell culture supernatants by enzyme-linked immunosorbent assay (ELISA). A higher frequency of enterocytes (EpCam+ cells) was observed in UC patients compared to CD or HC. An expansion of enterocytes producing IL-15 and TNF-α were found in IBD patients compared to HC. A marked expression of IL-15 in the intestinal epithelium of IBD patients was further confirmed by immunohistochemistry. Myeloid dendritic (CD11c+) cells producing TNF-α and INF-γ were increased in IBD biopsies. Unexpectedly, only after a strong mitogen stimulus, as phytohaemagglutinin, the frequency of CD3+ cells producing IFN-γ was increased in IBD compared to control intestinal mucosa. Interestingly, functional studies performed on organ cultures of intestinal biopsies with neutralizing anti-IL-15 monoclonal antibody showed a marked reduction of mononuclear cell activation, proliferation of crypt enterocytes, as well as a reduction of TNF-α release in organ culture supernatants. In conclusion, we found that in the gut mucosa of IBD children both enterocytes and dendritic cells produce proinflammatory cytokines. The over-expression of IL-15 by enterocytes in IBD intestine and the reduced IBD inflammation by IL-15 blockage suggests that this cytokine could be a therapeutic target in IBD.

• Adolescent
• Biomarkers/metabolism
• Case-Control Studies
• Cells, Cultured
• Child
• Cytokines/metabolism
• Dendritic Cells/metabolism
• Enterocytes/metabolism
• Humans
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/metabolism
• Intestinal Mucosa/metabolism
• T-Lymphocytes/metabolism

• MIUR PRIN 2009-2011;

• Tight-junctions proteins
• ulcerative colitis
• vitamin D

• Adoptive Transfer
• Animals
• CD4-Positive T-Lymphocytes/immunology
• Cell Differentiation/immunology
• Colon/immunology
• Colon/metabolism
• Colon/pathology
• Cytokines/immunology
• Down-Regulation
• Flow Cytometry
• Forkhead Transcription Factors/immunology
• Forkhead Transcription Factors/metabolism
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/metabolism
• Inflammatory Bowel Diseases/pathology
• Interleukin-15/genetics
• Interleukin-15/immunology
• Mice
• Mice, Knockout
• Nuclear Receptor Subfamily 1, Group F, Member 3/immunology
• Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
• T-Lymphocytes, Regulatory/immunology
• Th1 Cells/immunology
• Th17 Cells/immunology

• Bacterial Infections/immunology
• CD8-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/metabolism
• Celiac Disease/immunology
• Celiac Disease/metabolism
• Diabetes Mellitus, Type 1/immunology
• Diabetes Mellitus, Type 1/metabolism
• Humans
• Immunity, Cellular/immunology
• Interleukin-15/immunology
• Interleukin-15/metabolism
• Interleukin-15 Receptor alpha Subunit/immunology
• Interleukin-15 Receptor alpha Subunit/metabolism
• Killer Cells, Natural/immunology
• Killer Cells, Natural/metabolism
• Models, Immunological
• Protein Binding/immunology
• Signal Transduction/immunology
• T-Lymphocytes/immunology
• T-Lymphocytes/metabolism
• Th1 Cells/immunology
• Th1 Cells/metabolism

• R01 DK067180 NIDDK NIH HHS
• P30 DK042086 NIDDK NIH HHS
• DK42086 NIDDK NIH HHS
• R01DK098435 NIDDK NIH HHS
• R01DK67180 NIDDK NIH HHS
• R01 DK098435 NIDDK NIH HHS

The search for biomarkers that characterize specific aspects of inflammatory bowel disease (IBD), has received substantial interest in the past years and is moving forward rapidly with the help of modern technologies. Nevertheless, there is a direct demand to identify adequate biomarkers for predicting and evaluating therapeutic response to different therapies. In this subset, pharmacogenetics deserves more attention as part of the endeavor to provide personalized medicine. The ultimate goal in this area is the adjustment of medication for a patient’s specific genetic background and thereby to improve drug efficacy and safety rates. The aim of the following review is to utilize the latest knowledge on immunopathogenesis of IBD and update the findings on the field of Immunology and Genetics, to evaluate the response to the different therapies. In the present article, more than 400 publications were reviewed but finally 287 included based on design, reproducibility (or expectancy to be reproducible and translationable into humans) or already measured in humans. A few tests have shown clinical applicability. Other, i.e., genetic associations for the different therapies in IBD have not yet shown consistent or robust results. In the close future it is anticipated that this, cellular and genetic material, as well as the determination of biomarkers will be implemented in an integrated molecular diagnostic and prognostic approach to manage IBD patients.

• Mucosal immunology
• Biomarkers
• Pharmacology
• Mode of action
• Therapeutic drug monitoring

• Animals
• Anti-Inflammatory Agents/adverse effects
• Anti-Inflammatory Agents/pharmacokinetics
• Anti-Inflammatory Agents/therapeutic use
• Biotransformation/genetics
• Diagnostic Imaging/methods
• Drug Monitoring/methods
• Gastrointestinal Agents/adverse effects
• Gastrointestinal Agents/pharmacokinetics
• Gastrointestinal Agents/therapeutic use
• Genetic Markers
• Genetic Predisposition to Disease
• Humans
• Inflammation Mediators/immunology
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/genetics
• Inflammatory Bowel Diseases/immunology
• Molecular Diagnostic Techniques
• Phenotype
• Predictive Value of Tests
• Treatment Outcome

• ULCERATIVE COLITIS

Interleukin-15 (IL-15) is a cytokine highly expressed in skeletal muscle. The objective of the present study was to investigate the development of muscle IL-15 expression in suckling piglets and in early weaning piglets (day 14) at each level, that is, mRNA, protein, and secretion. Eight litters (eight piglets per litter) of newborn healthy piglets (Large × White × Landrace) with a similar initial weight (1618.0 ± 140.1 g) were chosen and divided into two groups. Group one used suckling piglets that were killed, respectively, at days 1, 7, 14, 21, and group two used early (day 14) weaning piglets that were killed respectively, at days 15, 17, 19, 21. In group one, IL-15 gene expression levels increased significantly (P < 0.05) along with increased body weight over time. IL-15 protein expression levels in piglets at day 21 of age were higher (P < 0.05) than those in piglets at other ages, and there was no difference (P > 0.05) among piglets at other ages. These findings indicated that increased IL-15 mRNA expression did not result in a corresponding increase of its protein expression. In group two, which used early weaning piglets from days 15–19, IL-15 mRNA and protein expression levels increased constantly (P < 0.05) and were higher (P < 0.05) than those in suckling piglets. Moreover, there was no gain of body weight (P > 0.05) compared with suckling piglets at day 14 of age. However, IL-15 protein expression levels in early weaning piglets at day 21 of age dropped significantly (P < 0.05) to the levels as suckling piglets at day 21 of age, while body weight increased (P < 0.05) markedly to the levels as suckling piglets at day 21 of age. In both groups, the serum IL-15 levels of piglets decreased significantly (P < 0.01) over time. Taken together, our results indicate that IL-15 expression differs in suckling piglets and in weaning piglets. It is speculated that IL-15 may play an important role in counteracting the effects of early weaning stress.

• Inflammation
• Interleukin-15
• Piglets
• Weaning stress

• IL-15
• autoimmunity
• celiac disease
• cytotoxic T cells
• loss of oral tolerance
• tissue

• IL-15
• autoimmunity
• celiac disease
• cytotoxic T cells
• loss of oral tolerance
• tissue

Inflammatory bowel disease (IBD) results from a complex series of interactions between susceptibility genes, the environment, and the immune system. The host microbiome, as well as viruses and fungi, play important roles in the development of IBD either by causing inflammation directly or indirectly through an altered immune system. New technologies have allowed researchers to be able to quantify the various components of the microbiome, which will allow for future developments in the etiology of IBD. Various components of the mucosal immune system are implicated in the pathogenesis of IBD and include intestinal epithelial cells, innate lymphoid cells, cells of the innate (macrophages/monocytes, neutrophils, and dendritic cells) and adaptive (T-cells and B-cells) immune system, and their secreted mediators (cytokines and chemokines). Either a mucosal susceptibility or defect in sampling of gut luminal antigen, possibly through the process of autophagy, leads to activation of innate immune response that may be mediated by enhanced toll-like receptor activity. The antigen presenting cells then mediate the differentiation of naïve T-cells into effector T helper (Th) cells, including Th1, Th2, and Th17, which alter gut homeostasis and lead to IBD. In this review, the effects of these components in the immunopathogenesis of IBD will be discussed.

• Inflammatory bowel disease
• Crohn’s disease
• Ulcerative colitis
• Microbiome
• Autophagy
• T helper 17
• Innate immune system
• Adaptive immune system
• Innate lymphoid cells
• TL1A

• Adaptive Immunity
• Animals
• Autophagy
• Bacteria/immunology
• Humans
• Immunity, Innate
• Immunity, Mucosal
• Inflammation Mediators/metabolism
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/microbiology
• Inflammatory Bowel Diseases/pathology
• Intestinal Mucosa/immunology
• Intestinal Mucosa/microbiology
• Intestinal Mucosa/pathology
• Intestines/immunology
• Intestines/microbiology
• Intestines/pathology
• Microbiota
• Risk Factors
• Signal Transduction
• T-Lymphocytes, Helper-Inducer/immunology

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is characterized by chronic relapsing intestinal inflammation. It has been a worldwide health-care problem with a continually increasing incidence. It is thought that IBD results from an aberrant and continuing immune response to the microbes in the gut, catalyzed by the genetic susceptibility of the individual. Although the etiology of IBD remains largely unknown, it involves a complex interaction between the genetic, environmental or microbial factors and the immune responses. Of the four components of IBD pathogenesis, most rapid progress has been made in the genetic study of gut inflammation. The latest internationally collaborative studies have ascertained 163 susceptibility gene loci for IBD. The genes implicated in childhood-onset and adult-onset IBD overlap, suggesting similar genetic predispositions. However, the fact that genetic factors account for only a portion of overall disease variance indicates that microbial and environmental factors may interact with genetic elements in the pathogenesis of IBD. Meanwhile, the adaptive immune response has been classically considered to play a major role in the pathogenesis of IBD, as new studies in immunology and genetics have clarified that the innate immune response maintains the same importance in inducing gut inflammation. Recent progress in understanding IBD pathogenesis sheds lights on relevant disease mechanisms, including the innate and adaptive immunity, and the interactions between genetic factors and microbial and environmental cues. In this review, we provide an update on the major advances that have occurred in above areas.

• Inflammatory bowel disease
• Ulcerative colitis
• Crohn’s disease
• Pathogenesis
• Genetics
• Microbial factors
• Immune responses

• Adaptive Immunity
• Animals
• Environment
• Genetic Predisposition to Disease
• Humans
• Immunity, Innate
• Inflammatory Bowel Diseases/etiology
• Inflammatory Bowel Diseases/genetics
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/microbiology
• Intestines/immunology
• Intestines/microbiology
• Prognosis
• Risk Factors

• Celiac Disease
• Colorectal cancer
• IL-15
• Immunological niche
• Inflammatory Bowel Diseases

• Autophagy
• CD
• Crohn's disease
• Cytokines
• DC
• GWAS
• IBD
• IFN
• IL
• ILC
• Innate lymphoid cell
• MyD88
• NF
• NK
• NLR
• NOD
• NOD-like receptor
• PAMP
• PRR
• T cell
• T helper cell type
• TLR
• TNF
• Th
• Toll-like receptor
• Treg
• UC
• dendritic cell
• genome-wide association studies
• iNKT
• inflammatory bowel disease
• innate lymphoid cell
• interferon
• interleukin
• invariant natural killer T
• myeloid differentiation primary response gene 88
• natural killer
• nuclear factor
• nucleotide-binding oligomerization domain
• pathogen associated molecular pattern
• pattern recognition receptor
• regulatory T cell
• tumor necrosis factor
• ulcerative colitis

Fibrosis is a serious consequence of Crohn’s disease (CD), often necessitating surgical resection. We examined the hypothesis that IL-13 may promote collagen accumulation within the CD muscle microenvironment.

Factors potentially modulating collagen deposition were examined in intestinal tissue samples from fibrotic (f) CD and compared with cancer control (C), ulcerative colitis (UC) and uninvolved (u) CD. Mechanisms attributable to IL-13 were analysed using cell lines derived from uninvolved muscle tissue and tissue explants.

In fCD muscle extracts, collagen synthesis was significantly increased compared to other groups, but MMP-2 was not co-ordinately increased. IL-13 transcripts were highest in fCD muscle compared to muscle from other groups. IL-13 receptor (R) α1 was expressed by intestinal muscle smooth muscle, nerve and KIR⁺ cells. Fibroblasts from intestinal muscle expressed Rα1, phosphorylated STAT6 in response to IL-13, and subsequently down-regulated MMP-2 and TNF-α-induced MMP-1 and MMP-9 synthesis. Cells with the phenotype KIR⁺CD45⁺CD56^+/−CD3⁻ were significantly increased in fCD muscle compared to all other groups, expressed Rα1 and membrane IL-13, and transcribed high levels of IL-13. In explanted CD muscle, these cells did not phosphorylate STAT6 in response to exogenous IL-13.

The data indicate that in fibrotic intestinal muscle of Crohn’s patients, the IL-13 pathway is stimulated, involving a novel population of infiltrating IL-13Rα1⁺, KIR⁺ innate lymphoid cells, producing IL-13 which inhibits fibroblast MMP synthesis. Consequently, matrix degradation is down-regulated and this leads to excessive collagen deposition.

• Adolescent
• Adult
• Aged
• Collagen/biosynthesis
• Collagen/metabolism
• Crohn Disease/immunology
• Crohn Disease/metabolism
• Crohn Disease/pathology
• Down-Regulation
• Female
• Fibroblasts/metabolism
• Fibroblasts/pathology
• Fibrosis
• Humans
• Interleukin-13/metabolism
• Interleukin-13 Receptor alpha1 Subunit/metabolism
• Intestinal Mucosa/immunology
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/pathology
• Lymphocytes/cytology
• Lymphocytes/immunology
• Male
• Matrix Metalloproteinases/biosynthesis
• Middle Aged
• Muscles/metabolism
• Muscles/pathology
• Young Adult

• ulcerative colitis
• stat6 transcription factor
• suberoylanilide hydroxamic acid
• interleukin-13
• cell membrane permeability

• Apoptosis/drug effects
• Blotting, Western
• Case-Control Studies
• Cells, Cultured
• Child
• Claudins/genetics
• Claudins/metabolism
• Colitis, Ulcerative/genetics
• Colitis, Ulcerative/metabolism
• Colitis, Ulcerative/pathology
• Colon/drug effects
• Colon/metabolism
• Colon/pathology
• Crohn Disease/genetics
• Crohn Disease/metabolism
• Crohn Disease/pathology
• Epithelial Cells/drug effects
• Epithelial Cells/metabolism
• Epithelial Cells/pathology
• Female
• Humans
• Hydroxamic Acids/pharmacology
• Immunoenzyme Techniques
• Interleukin-13/pharmacology
• Male
• Phosphorylation
• RNA, Messenger/genetics
• RNA, Small Interfering/genetics
• Real-Time Polymerase Chain Reaction
• STAT6 Transcription Factor/antagonists & inhibitors
• STAT6 Transcription Factor/genetics
• STAT6 Transcription Factor/metabolism
• Signal Transduction
• Up-Regulation
• Vorinostat

• P30 DK058404-05 NIDDK NIH HHS
• T32 DK007673 NIDDK NIH HHS
• 2T32DK007673-16 NIDDK NIH HHS
• R01 AT004821 NCCIH NIH HHS
• K01 DK077956-05 NIDDK NIH HHS
• K01DK077956 NIDDK NIH HHS
• P30DK058404 NIDDK NIH HHS
• R01 AT004821-02S1 NCCIH NIH HHS
• 5R01AT004821-03 NCCIH NIH HHS
• T32 DK007673-16 NIDDK NIH HHS
• K01 DK077956 NIDDK NIH HHS
• R03 DK090295 NIDDK NIH HHS
• P30 DK058404 NIDDK NIH HHS
• R01 AT004821-03 NCCIH NIH HHS
• 3R01AT004821-02S1 NCCIH NIH HHS
• R01 DK056008 NIDDK NIH HHS
• R01DK056008 NIDDK NIH HHS
• R01 DK056008-12 NIDDK NIH HHS

• Animals
• Cells, Cultured
• Crohn Disease/drug therapy
• Crohn Disease/immunology
• Crohn Disease/pathology
• Cytokines/genetics
• Cytokines/metabolism
• Dexamethasone/pharmacology
• Disease Models, Animal
• Eosinophils/immunology
• Eosinophils/pathology
• Female
• Flow Cytometry
• GATA3 Transcription Factor/genetics
• GATA3 Transcription Factor/metabolism
• Ileitis/drug therapy
• Ileitis/immunology
• Ileitis/pathology
• Immunologic Memory/drug effects
• Mice
• Mice, Mutant Strains
• Phenotype
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Reverse Transcriptase Polymerase Chain Reaction
• Th1 Cells/immunology
• Th2 Cells/immunology

• R01 DK062245 NIDDK NIH HHS
• R01 DK062245-05S1 NIDDK NIH HHS
• K08 DK067254 NIDDK NIH HHS
• DK073280 NIDDK NIH HHS
• DK 62245 NIDDK NIH HHS
• R03 DK073280 NIDDK NIH HHS
• DK067254 NIDDK NIH HHS
• R03 DK073280-03 NIDDK NIH HHS
• K08 DK067254-05S1 NIDDK NIH HHS
• R01 DK080212 NIDDK NIH HHS
• I01 BX001051 BLRD VA

AIM: To investigate the role of nuclear factor of activated T cell 2 (NFAT2), the major NFAT protein in peripheral T cells, in sustained T cell activation and intractable inflammation in human ulcerative colitis (UC).

METHODS: We used two-dimensional gel-electrophoresis, immunohistochemistry, double immunohistochemical staining, and confocal microscopy to inspect the expression of NFAT2 in 107, 15, 48 and 5 cases of UC, Crohn’s disease (CD), non-specific colitis, and 5 healthy individuals, respectively.

RESULTS: Up-regulation with profound nucleo-translocation/activation of NFAT2 of lamina propria mononuclear cells (LPMC) of colonic mucosa was found specifically in the affected colonic mucosa from patients with UC, as compared to CD or NC (P < 0.001, Kruskal-Wallis test). Nucleo-translocation/activation of NFAT2 primarily occurred in CD8+T, but was less prominent in CD4+ T cells or CD20+B cells. It was strongly associated with the disease activity, including endoscopic stage (τ = 0.2145, P = 0.0281) and histologic grade (τ = 0.4167, P < 0.001).

CONCLUSION: We disclose for the first time the nucleo-translocation/activatin of NFAT2 in lamina propria mononuclear cells in ulcerative colitis. Activation of NFAT2 was specific for ulcerative colitis and highly associated with disease activity. Since activation of NFAT2 is implicated in an auto-regulatory positive feedback loop of sustained T-cell activation and NFAT proteins play key roles in the calcium/calcineurin signaling pathways, our results not only provide new insights into the mechanism for sustained intractable inflammation, but also suggest the calcium-calcineurin/NFAT pathway as a new therapeutic target for ulcerative colitis.

• Nuclear factor of activated T cells
• Ulcerative colitis
• Inflammatory bowel disease
• Nuclear factor of activated T cells c1
• Nuclear factor of activated T cells 2

• Adult
• Animals
• Apoptosis
• Cell Proliferation
• Colitis, Ulcerative/genetics
• Colitis, Ulcerative/immunology
• Colitis, Ulcerative/metabolism
• Colitis, Ulcerative/pathology
• Endoplasmic Reticulum/pathology
• Endoplasmic Reticulum/ultrastructure
• Gene Expression Regulation
• Genetic Predisposition to Disease
• Goblet Cells/pathology
• Humans
• Inflammation
• Intestinal Mucosa/pathology
• Intestinal Mucosa/ultrastructure
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Mucin-2
• Mucins/chemistry
• Mucins/genetics
• Mucins/metabolism
• Mutation/genetics
• Protein Folding
• Protein Precursors/metabolism
• Protein Structure, Quaternary

• Animals
• Animals, Domestic/growth & development
• Body Composition/immunology
• Body Composition/physiology
• Interleukin-15/biosynthesis
• Interleukin-15/physiology
• Muscle, Skeletal/immunology
• Muscle, Skeletal/physiology
• Signal Transduction

• R01 AG024136 NIA NIH HHS

• Case-Control Studies
• Colitis, Ulcerative/immunology
• Crohn Disease/immunology
• Cytokines/metabolism
• Humans
• Intestinal Mucosa/immunology
• Killer Cells, Natural/metabolism
• RNA, Messenger/metabolism
• Receptors, Antigen, T-Cell, alpha-beta/metabolism
• T-Lymphocyte Subsets/metabolism

• Animals
• Apoptosis/immunology
• Blotting, Western
• Caspase 3/metabolism
• Cell Line
• Colitis/immunology
• Colitis/pathology
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Female
• Flow Cytometry
• Humans
• In Situ Nick-End Labeling
• Interferon-gamma/metabolism
• Interleukin-15/immunology
• Interleukin-6/metabolism
• Intestinal Mucosa/immunology
• Lymph Nodes/immunology
• Lymphocyte Activation/immunology
• Mesentery/immunology
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Reverse Transcriptase Polymerase Chain Reaction
• T-Lymphocytes/immunology
• Tumor Necrosis Factor-alpha/metabolism

• Cell Line, Tumor
• Cytokines/physiology
• Down-Regulation/immunology
• Gene Expression Regulation, Neoplastic/immunology
• HT29 Cells
• Humans
• Interleukin-4/physiology
• Intestinal Mucosa/cytology
• Intestinal Mucosa/immunology
• Intestinal Mucosa/metabolism
• RNA, Messenger/metabolism
• Th2 Cells/immunology
• Th2 Cells/metabolism
• Toll-Like Receptors/antagonists & inhibitors
• Toll-Like Receptors/biosynthesis
• Toll-Like Receptors/physiology
• U937 Cells

• DK 043351 NIDDK NIH HHS
• DK 069344 NIDDK NIH HHS
• DK 07191 NIDDK NIH HHS

N/A

• N/A

• Base Sequence
• Blotting, Western
• Cell Division
• Chromones/pharmacology
• Claudin-3
• Claudin-4
• Claudins
• Colon/cytology
• Colon/physiopathology
• DNA Primers
• Electrophoresis, Polyacrylamide Gel
• Enzyme Inhibitors/pharmacology
• Epithelial Cells/physiology
• Humans
• Immunohistochemistry
• Inflammation Mediators/physiology
• Interferon-gamma/physiology
• Interleukin-13/antagonists & inhibitors
• Interleukin-13/physiology
• Intestinal Mucosa/physiopathology
• Membrane Proteins/physiology
• Morpholines/pharmacology
• Phosphoinositide-3 Kinase Inhibitors
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Necrosis Factor-alpha/physiology

N/A

• N/A