• Anti-inflammatory effect
• Grass carp (Ctenopharyngodon idella)
• Interleukin-23 receptor
• Polyclonal antibody
• Proinflammatory activity

• Animals
• Humans
• Amino Acid Sequence
• Carps/genetics
• Carps/metabolism
• Lipopolysaccharides
• Inflammation/genetics
• Interleukin-23
• Fish Diseases/genetics
• Fish Proteins/metabolism
• Immunity, Innate
• Mammals/metabolism

• Detection
• Gut inflammation
• High-throughput
• Omics
• Therapeutics

• Humans
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/genetics
• Genomics
• Proteomics/methods
• Metabolomics/methods
• Gene Expression Profiling

• Inflammatory bowel disease
• phase II and phase III trials
• treatment
• ulcerative colitis

• Crohn’s disease
• JAK2
• circSMAD4
• colitis
• intestinal barrier function
• miR-135a-5p

The pathophysiology of inflammatory bowel diseases (IBD) reflects a balance between mucosal injury and reparative mechanisms. Some regenerating gene (Reg) family members (REG Iα, REG Iβ and REG IV) are expressed in Crohn's disease (CD) and ulcerative colitis (UC) and involved as proliferative mucosal factors in IBD. We revealed that REG Iα and REG Iβ were induced in cell culture system by IL‐6/IL‐22. Although REG IV was upregulated in IBD biopsy samples, the upregulation of REG IV was not at all induced in cell culture by autoimmune‐related cytokines such as IL‐6, IL‐22 and TNFα. Here, we analysed REG IV expression in LS‐174 T and HT‐29 human intestinal epithelial cells by real‐time RT–PCR and elisa. REG IV expression was induced by lipopolysaccharide (LPS). However, LPS did not activate REG IV promoter activity. As the LPS‐induced upregulation of REG IV was considered to be regulated post‐transcriptionally, we searched targeted microRNA (miR), which revealed that REG IV mRNA has a potential target sequence for miR‐24. We measured the miR‐24 level of LPS‐treated cells and found that the level was significantly lower. The LPS‐induced increase of REG IV mRNA was abolished by the introduction of miR‐24 mimic but not by non‐specific control RNA.

• REG IV
• LPS
• inflammatory bowel diseases
• microRNA-24

Background: The pathological differences between Crohn’s disease (CD) and ulcerative colitis (UC) are substantial and unexplained yet. Here, we aimed to identify potential regulators that drive different pathogenesis of CD and UC by causal inference analysis of transcriptome data.

Methods: Kruskal–Wallis and Dunnett’s tests were performed to identify differentially expressed genes (DEGs) among CD patients, UC patients, and controls. Subsequently, differentially expressed pathways (DEPs) between CD and UC were identified and used to construct the interaction network of DEPs. Causal inference was performed to identify IBD subtype-regulators. The expression of the subtype-regulators and their downstream genes was validated by qRT-PCR with an independent cohort.

Results: Compared with the control group, we identified 1,352 and 2,081 DEGs in CD and UC groups, respectively. Multiple DEPs between CD and UC were closely related to inflammation-related pathways, such as NOD-like receptor signaling, IL-17 signaling, and chemokine signaling pathways. Based on the priori interaction network of DEPs, causal inference analysis identified IFNG and GBP5 as IBD subtype-regulators. The results with the discovery cohort showed that the expression level of IFNG, GBP5, and NLRP3 was significantly higher in the CD group than that in the UC group. The regulation relationships among IFNG, GBP5, and NLRP3 were confirmed with transcriptome data from an independent cohort and validated by qRT-PCR.

Conclusion: Our study suggests that IFNG and GBP5 were IBD subtype-regulators that trigger more intense innate immunity and inflammatory responses in CD than those in UC. Our findings reveal pathomechanical differences between CD and UC that may contribute to personalized treatment for CD and UC.

• Crohn’s disease
• IBD subtype-regulator
• causal inference
• inflammatory bowel disease
• ulcerative colitis

Nonresolving inflammation is a critical driver of several chronic inflammatory diseases, including inflammatory bowel diseases (IBD). This unresolved inflammation may result from the persistence of an initiating stimulus or from the alteration of the resolution phase of inflammation. Elimination of apoptotic cells by macrophages (a process called efferocytosis) is a critical step in the resolution phase of inflammation. Efferocytosis participates in macrophage reprogramming and favors the release of numerous pro-resolving factors. These pro-resolving factors exert therapeutic effects in experimental autoimmune arthritis. Here, we propose to evaluate the efficacy of pro-resolving factors produced by macrophages after efferocytosis, a secretome called SuperMApo, in two IBD models, namely dextran sodium sulfate (DSS)-induced and T cell transfer-induced colitis. Reintroducing these pro-resolving factors was sufficient to decrease clinical, endoscopic and histological colitis scores in ongoing naive T cell-transfer-induced colitis and in DSS-induced colitis. Mouse primary fibroblasts isolated from the colon demonstrated enhanced healing properties in the presence of SuperMApo, as attested by their increased migratory, proliferative and contractive properties. This was confirmed by the use of human fibroblasts isolated from patients with IBD. Exposure of an intestinal epithelial cell (IEC) line to these pro-resolving factors increased their proliferative properties and IEC acquired the capacity to capture apoptotic cells. The improvement of wound healing properties induced by SuperMApo was confirmed in vivo in a biopsy forceps-wound colonic mucosa model. Further in vivo analysis in naive T cell transfer-induced colitis model demonstrated an improvement of intestinal barrier permeability after administration of SuperMApo, an intestinal cell proliferation and an increase of α-SMA expression by fibroblasts, as well as a reduction of the transcript coding for fibronectin (Fn1). Finally, we identified TGF-β, IGF-I and VEGF among SuperMApo as necessary to favor mucosal healing and confirmed their role both in vitro (using neutralizing antibodies) and in vivo by depleting these factors from efferocytic macrophage secretome using antibody-coated microbeads. These growth factors only explained some of the beneficial effects induced by factors released by efferocytic macrophages. Overall, the administration of pro-resolving factors released by efferocytic macrophages limits intestinal inflammation and enhance tissue repair, which represents an innovative treatment of IBD.

• Actins/biosynthesis
• Actins/genetics
• Animals
• Biological Factors/pharmacology
• Biological Factors/physiology
• CD4-Positive T-Lymphocytes/immunology
• CD4-Positive T-Lymphocytes/transplantation
• Cell Division/drug effects
• Cell Line
• Colitis/chemically induced
• Colitis/etiology
• Colitis/immunology
• Cytophagocytosis/physiology
• DNA-Binding Proteins/deficiency
• Dextran Sulfate/toxicity
• Disease Models, Animal
• Epithelial Cells/drug effects
• Epithelial Cells/physiology
• Female
• Fibroblasts/physiology
• Fibronectins/biosynthesis
• Fibronectins/genetics
• Humans
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/physiopathology
• Inflammatory Bowel Diseases/therapy
• Intestinal Mucosa/cytology
• Intestinal Mucosa/injuries
• Lymphocyte Transfusion/adverse effects
• Macrophages/physiology
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Specific Pathogen-Free Organisms
• Wound Healing/physiology

• Agence Nationale de la Recherche
• Conseil régional de Bourgogne-Franche-Comté
• Bpifrance
• European Regional Development Fund

• Autoimmune diseases
• IL-23
• Inflammatory bowel disease
• Psoriasis
• Rheumatoid arthritis

• Animals
• Autoimmune Diseases/drug therapy
• Autoimmune Diseases/immunology
• Humans
• Interleukin-23/antagonists & inhibitors
• Interleukin-23/immunology

• STAT3
• antimicrobial peptide (AMP)
• innate immunity
• interleukin-22
• microbiology
• mucosal immunology
• signal transduction

• Epithelial Cells/immunology
• Epithelial Cells/pathology
• Escherichia coli/immunology
• Escherichia coli Infections/immunology
• Escherichia coli Infections/pathology
• Female
• Gene Expression Regulation/immunology
• HCT116 Cells
• Humans
• Interleukins/immunology
• Intestinal Mucosa/immunology
• Klebsiella Infections/immunology
• Klebsiella Infections/pathology
• Klebsiella pneumoniae/immunology
• Lipocalin-2/immunology
• Lymphocytes/immunology
• Lymphocytes/pathology
• Male
• NF-kappa B/immunology
• STAT3 Transcription Factor/immunology
• Interleukin-22

• Scandinavian Society for Antimicrobial Chemotherapy Foundation (SSAC Foundation)
• Karolinska Institutet (KI)

• Anti-CD40
• Colitis
• IBD
• IL-22
• IL-23
• Inflammation
• Innate immunity

• Colon cancer
• Cytokines
• IBD
• IL-23
• Immune response

The chemokine C-C motif ligand 20 (CCL20) is increased in the colonic mucosa during active inflammatory bowel disease (IBD) and can be found both in the epithelium and immune cells in the lamina propria. The present study investigated CCL20 and C-C motif Chemokine Receptor 6 (CCR6) in peripheral blood mononuclear cells (PBMCs) (n = 40) from IBD patients and healthy controls, to identify inductors of CCL20 release encountered in a local proinflammatory environment. CCL20 release from PBMCs was increased when activating TLR2/1 or NOD2, suggesting that CCL20 is part of a first line response to danger-associated molecular patterns also in immune cells. Overall, ulcerative colitis (UC) had a significantly stronger CCL20 release than Crohn’s disease (CD) (+242%, p < 0.01), indicating that the CCL20-CCR6 axis may be more involved in UC. The CCL20 receptor CCR6 is essential for the chemotactic function of CCL20. UC with active inflammation had significantly decreased CCR6 expression and a reduction in CCR6⁺ cells in circulation, indicating chemoattraction of CCR6⁺ cells from circulation towards peripheral tissues. We further examined CCL20 induced release of cytokines from PBMCs. Stimulation with CCL20 combined with TNF increased IL-1β release from PBMCs. By attracting additional immune cells, as well as inducing proinflammatory IL-1β release from immune cells, CCL20 may protract the inflammatory response in ulcerative colitis.

• CCL20
• CCR6
• inflammatory bowel disease
• interleukin-1β
• peripheral blood mononuclear cells

• Adult
• Aged
• Case-Control Studies
• Chemokine CCL20/metabolism
• Colitis, Ulcerative/blood
• Colitis, Ulcerative/metabolism
• Female
• Humans
• Interleukin-1beta/metabolism
• Male
• Middle Aged
• Monocytes/metabolism
• Nod2 Signaling Adaptor Protein/metabolism
• Receptors, CCR6/metabolism
• Toll-Like Receptors/metabolism

• Activation
• Apoptosis
• BV-2 microglial cells
• Oligodendrocyte precursor cells
• S100A8/A9

• Animals
• Apoptosis
• Calgranulin A/metabolism
• Calgranulin A/physiology
• Calgranulin B/metabolism
• Calgranulin B/physiology
• Cytokines/metabolism
• Female
• Inflammation
• Interleukin-1beta/metabolism
• Macrophage Activation
• Macrophages/pathology
• Male
• Microglia/physiology
• NF-kappa B/metabolism
• Oligodendrocyte Precursor Cells/drug effects
• Oligodendrocyte Precursor Cells/metabolism
• Phosphorylation
• Primary Cell Culture
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Tumor Necrosis Factor-alpha/metabolism

• Expression profiling
• IL23/ IL17/TLR9
• Inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic inflammatory disease, in which the intestinal epithelium loses its barrier function. Given the existence of the oxygen gradient in the intestinal epithelium and that inflammation further contributes to the tissue hypoxia, we investigated the role of hypoxia-inducible factor (HIF), a transcription factor activated under hypoxic conditions in myeloid cells, in the progression of IBD. To do this, we utilized myeloid-specific knockout (KO) mice targeting HIF pathways, created by a Cre-loxP system with human MRP8 (hMRP8), an intracellular calcium-binding protein, as the myeloid promoter. By feeding 5% dextran sodium sulfate (DSS) to hMRP8 von Hippel Lindau (Vhl) KO mice, in which HIF-1α and HIF-2α are constitutively activated in myeloid cells, we found that these mice were highly susceptible to DSS-induced colitis, demonstrating greater body weight loss, increased mortality, faster onset of rectal bleeding, shortened colon length, and increased CD11b- or Gr-1-positive myeloid cells in the colon compared with wild-type (WT) mice. These parameters were restored to, if not better than, the WT levels when we examined hMRP8 Hif-1a KO mice upon 5% DSS feeding. hMRP8 Hif-2a KO mice, on the other hand, exhibited a similar degree of DSS-induced colitis to that of WT mice. Lastly, when DSS was given together with azoxymethane to induce tumorigenesis in the colon, we found that hMRP8 Hif-1a KO mice exhibited comparable levels of colorectal tumors to those of WT mice, indicating that HIF-1α in myeloid cells is dispensable for tumorigenesis. Collectively, our results suggest that HIF-1α activation in myeloid cells critically regulates IBD progression.

Summary: We challenged myeloid-specific knockout mice targeting the hypoxia-inducible factor (HIF) pathway to dextran sodium sulfate-induced colitis, demonstrating that HIF-1α, but not HIF-2α, activation in myeloid cells regulates colitis severity in mice.

• malnutrition
• growth
• inflammatory biomarkers
• gut function
• enteric pathogens

Cells universally adapt to ischemic conditions by turning on a transcription factor hypoxia-inducible factor (HIF), in which its role is known to differ widely across many different types of cells. Given that microglia have been reported as an essential mediator of neuroinflammation in many brain diseases, we examined the role of HIF in microglia in the progression of an acute phase of ischemic stroke by challenging our novel strains of myeloid-specific Hif-1α or Hif-2α knockout (KO) mice created by Cre-loxP system via middle cerebral artery occlusion (MCAO). We observed that Hif-1α but not Hif-2α KO mice exhibited an improved recovery compared to wild-type (WT) mice determined by behavioral tests. Immunostaining analyses revealed that there were increased numbers of both mature and immature neurons while microglia and apoptotic cells were significantly decreased in the dentate gyrus of Hif-1α KO mice following MCAO. By isolating microglia with fluorescence-activated cell sorter, we found that HIF-1α-deficient microglia were impaired in phagocytosis, reactive oxygen species (ROS) production, and tumor necrosis factor-α (TNF-α) secretion. We further observed a significant decrease in the expression of Cd36 and milk fat globule-epidermal growth factor 8 (Mfg-e8) genes, both of which contain hypoxia-responsive element (HRE). Knocking down either of these genes in BV2 microglial cells was sufficient to abrogate HIF-mediated increase in phagocytosis, production of intracellular ROS, or TNF-α secretion. Our results therefore suggest that HIF-1α in microglia is a novel therapeutic target to protect neuronal survival following an acute phase of ischemic stroke.

• hypoxia-inducible factor-1α (HIF-1α)
• microglia
• phagocytosis
• stroke

• Clinical Trial
• IL22
• IL23
• Phase II

• Adult
• Antibodies, Monoclonal/adverse effects
• Antibodies, Monoclonal/therapeutic use
• Antibodies, Monoclonal, Humanized
• Crohn Disease/drug therapy
• Double-Blind Method
• Female
• Headache/chemically induced
• Humans
• Interleukin-23/antagonists & inhibitors
• Interleukins/blood
• Male
• Middle Aged
• Nasopharyngitis/chemically induced
• Retreatment
• Severity of Illness Index
• Treatment Outcome
• Young Adult
• Interleukin-22

Bovine paratuberculosis (PTB) is a chronic enteric inflammatory disease of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP) that causes large economic losses in the dairy industry. Spread of PTB is mainly provoked by a long subclinical stage during which MAP is shed into the environment with feces; accordingly, detection of subclinical animals is very important to its control. However, current diagnostic methods are not suitable for detection of subclinical animals. Therefore, the current study was conducted to develop a diagnostic method for analysis of the expression of genes of prognostic potential biomarker candidates in the whole blood of cattle naturally infected with MAP. Real-time PCR with nine potential biomarker candidates was developed for the diagnosis of MAP subclinical infection. Animals were divided into four groups based on fecal MAP PCR and serum ELISA. Eight genes (Timp1, Hp, Serpine1, Tfrc, Mmp9, Defb1, Defb10, and S100a8) were up-regulated in MAP-infected cattle (p <0.05). Moreover, ROC analysis revealed that eight genes (Timp1, Hp, Serpine1, Tfrc, Mmp9, Defb1, Defb10, and S100a8) showed fair diagnostic performance (AUC≥0.8). Four biomarkers (Timp1, S100a8, Defb1, and Defb10) showed the highest diagnostic accuracy in the PCR positive and ELISA negative group (PN group) and three biomarkers (Tfrc, Hp, and Serpine1) showed the highest diagnostic accuracy in the PCR negative and ELISA positive group (NP group). Moreover, three biomarkers (S100a8, Hp, and Defb10) were considered the most reliable for the PCR positive and ELISA positive group (PP group). Taken together, our data suggest that real-time PCR based on eight biomarkers (Timp1, Hp, Serpine1, Tfrc, Mmp9, Defb1, Defb10, and S100a8) might be useful for diagnosis of JD, including subclinical stage cases.

• Animals
• Asymptomatic Infections
• Biomarkers/analysis
• Biomarkers/blood
• Cattle
• Cattle Diseases/diagnosis
• Cattle Diseases/microbiology
• Enzyme-Linked Immunosorbent Assay/veterinary
• Feces/chemistry
• Feces/microbiology
• Female
• Mycobacterium avium subsp. paratuberculosis/genetics
• Paratuberculosis/diagnosis
• Paratuberculosis/microbiology
• Real-Time Polymerase Chain Reaction/methods
• Real-Time Polymerase Chain Reaction/veterinary
• Reproducibility of Results
• Sensitivity and Specificity

• Rural Development Administration
• Korea Goverment
• Seoul National University
• National Research Foundation

• IBD
• Mip-3α
• TGF-β

• Cell Line
• Chemokine CCL20/blood
• Chemokine CCL20/metabolism
• Crohn Disease/drug therapy
• Crohn Disease/metabolism
• Double-Blind Method
• Humans
• Intestinal Mucosa/drug effects
• Intestinal Mucosa/metabolism
• Oligonucleotides/therapeutic use
• Smad7 Protein/antagonists & inhibitors
• Transforming Growth Factor beta1/metabolism
• Treatment Outcome

• DMBT1
• biliary tract cancer
• extrahepatic cholangiocarcinoma
• intrahepatic cholangiocarcinoma

• Cardiac surgery
• Cytokine
• Il-10
• Il-23
• Inflammation
• Necrotizing enterocolitis

Lipocalin 2 (Lcn2), also called neutrophil gelatinase B-associated lipocalin (NGAL), is an anti-microbial peptide originally identified in neutrophil granules. Although Lcn2/NGAL expression is increased in the inflamed intestinal tissues of patients with inflammatory bowel disease, the role of Lcn2/NGAL in the development of intestinal inflammation remains unclear. Here we investigated the role of Lcn2/NGAL in intestinal inflammation using a spontaneous mouse colitis model, interleukin-10 knock out (IL-10 KO) mice. Lcn2 expression in the colonic tissues of IL-10 KO mice increased with the development of colitis. Lcn2/IL-10 double-KO mice showed a more rapid onset and development of colitis compared to IL-10 KO mice. Lcn2 enhanced phagocytic bacterial clearance in macrophages in vitro after infection with Escherichia coli. Transfer of Lcn2-repleted macrophages prevented the development of colitis in Lcn2/IL-10 double-KO mice in vivo. Our findings revealed that Lcn2 prevents the development of intestinal inflammation. One crucial factor seems to be the enhancement of phagocytic bacterial clearance in macrophages by Lcn2.

Innate lymphoid cells (ILCs) contribute to host defence and tissue repair but can induce immunopathology. Recent work has revealed tissue-specific roles for ILCs; however, the question of how a small population has large effects on immune homeostasis remains unclear. We identify two mechanisms that ILC3s utilise to exert their effects within intestinal tissue. ILC-driven colitis depends on production of granulocyte macrophage-colony stimulating factor (GM-CSF), which recruits and maintains intestinal inflammatory monocytes. ILCs present in the intestine also enter and exit cryptopatches in a highly dynamic process. During colitis, ILC3s mobilize from cryptopatches, a process that can be inhibited by blocking GM-CSF, and mobilization precedes inflammatory foci elsewhere in the tissue. Together these data identify the IL-23R/GM-CSF axis within ILC3 as a key control point in the accumulation of innate effector cells in the intestine and in the spatio-temporal dynamics of ILCs in the intestinal inflammatory response.

DOI:http://dx.doi.org/10.7554/eLife.10066.001

Crohn’s disease and ulcerative colitis are diseases in which the body’s own immune system causes inflammation of the large intestine. These autoimmune diseases can be severely debilitating and difficult to treat. However an improved understanding of the factors that contribute to the intestinal inflammation may lead to new and effective treatments.

Immune cells called innate lymphoid cells were discovered recently, and shown quickly to play a role in host defense, tissue repair and inflammation regulation. Several groups of innate lymphoid cells are now known; each group is characterized by the genes that control the cell’s development and the small proteins (called cytokines) that the cells release. One group of innate lymphoid cells, the ILC3s, are generally found in the intestinal tract, albeit in small numbers. Given that innate lymphoid cells are known to manage inflammatory responses, it is possible that ILC3s contribute to intestinal inflammation. However, it remains unclear how such a small population of cells could so dramatically inflame the gut.

Pearson et al. now reveal two mechanisms that these innate lymphoid cells use to amplify the inflammatory response and exacerbate intestinal inflammation. First, in both mice and humans, ILC3s were found to be a key source of a cytokine called GM-CSF, which recruits additional immune cells that further promote intestinal inflammation. Secondly, while ILC3s were traditionally regarded as immobile immune cells, Pearson et al. discovered that these cells can move within the intestinal tissue and mobilize from their starting points within this tissue if they are activated. These two mechanisms could explain how ILC3s can trigger inflammation that occurs throughout the gut.

The experiments suggest that blocking production of the GM-CSF cytokine or altering ILC3 movement or activity may help reduce intestinal inflammation. However, the use of GM-CSF blocking drugs to protect against colitis and similar conditions could be problematic, because GM-CSF also plays an important protective role in the intestines. Nevertheless, clinical trials are underway to investigate the use of anti-GM-CSF drugs to treat other inflammatory conditions (such as rheumatoid arthritis). These studies could offer insight into whether these drugs provide relief to trial participants who suffer from intestinal inflammation as well.

DOI:http://dx.doi.org/10.7554/eLife.10066.002

• colitis
• human
• immunology
• innate lymphoid cells
• live imaging
• mouse
• mucosal immunology

• Animals
• Autoimmune Diseases/metabolism
• Autoimmunity/physiology
• Disease Models, Animal
• Humans
• Interferon Regulatory Factors/physiology
• Mice

• 20892 Arthritis Research UK
• 20892 Versus Arthritis

• Acute-Phase Proteins
• Adaptor Proteins, Signal Transducing
• Adolescent
• Adult
• Aged
• Biomarkers/blood
• Colitis, Ulcerative/blood
• Colitis, Ulcerative/genetics
• Colitis, Ulcerative/immunology
• Colon/metabolism
• Crohn Disease/blood
• Crohn Disease/genetics
• Crohn Disease/immunology
• Epithelial Cells/metabolism
• Female
• Genotype
• Healthy Volunteers
• Humans
• I-kappa B Proteins/metabolism
• Interleukin-17/metabolism
• Interleukins/metabolism
• Lipocalin-2
• Lipocalins/blood
• Male
• Middle Aged
• Nuclear Proteins/metabolism
• Polymorphism, Genetic
• Proto-Oncogene Proteins/blood
• Receptors, Interleukin/genetics
• Receptors, Interleukin/metabolism
• Th17 Cells/immunology
• Tumor Necrosis Factor-alpha/metabolism
• Up-Regulation
• Young Adult
• Interleukin-22

• Diarrhoea
• Enterotoxigenic Escherichia coli
• Intestine
• Islet-derived regenerating protein
• Pig

• Caenorhabditis elegans
• gut microbiome
• intestinal pathogens
• iron supplementation
• lipocalin-2

• IBD
• Mouse Model
• Plasminogen
• UC

AIM: To evaluate the expression of dendritic cell (DCs) and interleukin (IL)-23 in ulcerative colitis (UC) to improve the diagnosis and treatment of UC.

METHODS: Sixty UC and 60 irritable bowel syndrome (IBS) colon tissue sections were used to detect the expression of S100⁺ DCs, CD83⁺ DCs and IL-23P19 by immunohistochemistry. The expression of IL-23P19 in the mucosa was compared between acute and chronic stages, between mild and severe type diseases, and between before and after mesalazine treatment in the UC group.

RESULTS: There was a statistical difference in the infiltrated densities of S100⁺ DCs, CD83⁺ DCs and IL-23P19 cells between the UC group and IBS group (27.48 cells/mm² ± 9.23 cells/mm²vs 9.20 cells/mm² ± 3.91 cells/mm², 6.62 cells/mm² ± 2.59 cells/mm²vs 3.20 cells/mm² ± 1.59 cells/mm², 105.97 cells/mm² ± 25.30 cells/mm²vs 32.48 cells/mm² ± 11.61 cells/mm², P < 0.05). In the UC group, there was a statistical difference in the expression of IL-23P19 between acute and chronic stages, between mild and severe type diseases, and between before and after mesalazine treatment (113.83 cells/mm² ± 28.83 cells/mm²vs 49.35 cells/mm² ± 8.11 cells/mm², 75.03 cells/mm² ± 21.39 cells/mm²vs 117.38 cells/mm² ± 28.32 cells/mm², 109.89 cells/mm² ± 25.73 cells/mm²vs 47.25 cells/mm² ± 8.67 cells/mm², P < 0.05).

CONCLUSION: In UC colon tissue, the production of IL-23P19 increases with the increase in the infiltrated density and activity of DCs. The expression of IL-23P19 may be used as an indicator for evaluation of the disease stage, the degree of pathological changes and treatment efficacy in UC.

• Ulcerative colitis
• Dendritic cells
• Interleukin-23

• CROHN'S DISEASE
• IBD BASIC RESEARCH
• INFLAMMATORY MEDIATORS
• TNF-ALPHA

• Adalimumab
• Adult
• Aged
• Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
• Antibodies, Monoclonal/therapeutic use
• Antibodies, Monoclonal, Humanized/therapeutic use
• Colon/metabolism
• Crohn Disease/drug therapy
• Crohn Disease/genetics
• Crohn Disease/metabolism
• Female
• Gastrointestinal Agents/therapeutic use
• Gene Expression Profiling/methods
• Gene Expression Regulation/drug effects
• Humans
• Inflammation Mediators/metabolism
• Infliximab
• Interleukin-6/biosynthesis
• Interleukin-6/genetics
• Intestinal Mucosa/metabolism
• Male
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• Transcriptional Activation
• Treatment Failure
• Tumor Necrosis Factor-alpha/antagonists & inhibitors
• Young Adult

• crohn’s disease
• gene expression
• biomarker
• coefficient of variation
• sampling error
• proof-of-concept
• power

• allergy
• biomarkers
• neutrophil gelatinase-associated lipocalin
• pediatric inflammatory bowel disease

AIM: To investigate the correlation between the appearance of skin lesions and concentration of interleukin (IL)-17A, IL-23 and interferon-γ (IFN-γ) in Crohn’s disease (CD) patients during anti-tumor necrosis factor-α (TNF-α) therapy

METHODS: A prospective study included 30 adult patients with CD of Caucasian origin (19 men and 11 women; mean age ± SD 32.0 ± 8.6 years) during biological therapy with anti-TNF-α antibodies from January 2012 to March 2013. Eighteen patients were treated with infliximab, seven with adalimumab and five with certolizumab. Inclusion criteria were exacerbation of the underlying disease, Crohn’s Disease Activity Index over 300 and the ineffectiveness of previously used non-biological therapies. Patients with a history of psoriasis, atopic dermatitis and other autoimmune skin lesions were excluded from the study. The control group consisted of 12 healthy subjects. A diagnostic survey was carried out, blood tests and careful skin examination were performed, and the serum levels of IL-17, IL-23 and IFN-γ were measured using an enzyme-linked immunosorbent assays technique. Dermatoses that have developed in the course of biological therapy in patients who had no pre-existing skin lesions of similar character were qualified as skin lesions induced by anti-TNF-α therapy.

RESULTS: Skin manifestations occurred in 18 of CD patients during the anti-TNF-α therapy (60%), in the average time of 10.16 ± 3.42 mo following the beginning of the 52-wk treatment cycle. Skin lesions observed in CD patients during biological therapy included psoriasiform lesions (44.4%), and eczema forms lesions (22.2%). In CD patients with drug induced skin lesions significantly higher levels of hemoglobin (13.3 ± 1.5 g/dL vs 10.8 ± 1.9 g/dL, P = 0.018) and hematocrit (39.9% ± 4.5% vs 34.3% ± 5.4%, P = 0.01), as well as a significantly lower level of platelets (268 ± 62 × 10³/μL vs 408 ± 239 × 10³/μL, P = 0.046) was observed compared with CD patients without skin manifestations. The concentrations of IL-17A and IL-23 in CD patients with skin lesions developed under anti-TNF-α therapy were significantly higher compared to those in patients without lesions (IL-17A: 39.01 ± 7.03 pg/mL vs 25.71 ± 4.90 pg/mL, P = 0.00004; IL-23: 408.78 ± 94.13 pg/mL vs 312.15 ± 76.24 pg/mL, P = 0.00556).

CONCLUSION: Skin lesions in CD patients during biological therapy may result from significantly increased concentrations of IL-17A and IL-23, which are strongly associated with TNF-α/Th1 immune pathways.

• Biological therapy
• Crohn’s disease
• Interleukin 17A
• Interleukin 23
• Interferon γ
• Tumor necrosis factor-α

• Adalimumab
• Adult
• Anti-Inflammatory Agents/adverse effects
• Antibodies, Monoclonal/adverse effects
• Antibodies, Monoclonal, Humanized/adverse effects
• Case-Control Studies
• Crohn Disease/blood
• Crohn Disease/diagnosis
• Crohn Disease/drug therapy
• Crohn Disease/immunology
• Cytokines/blood
• Drug Eruptions/diagnosis
• Drug Eruptions/etiology
• Drug Eruptions/immunology
• Female
• Gastrointestinal Agents/adverse effects
• Humans
• Infliximab
• Interferon-gamma/blood
• Interleukin-17/blood
• Interleukin-23/blood
• Male
• Prospective Studies
• Risk Factors
• Severity of Illness Index
• Skin/drug effects
• Skin/immunology
• Skin/pathology
• Time Factors
• Treatment Outcome
• Tumor Necrosis Factor-alpha/antagonists & inhibitors
• Young Adult

Transition metal ions are essential micronutrients for all living organisms. In mammals, these ions are often protein-bound and sequestered within cells, limiting their availability to microbes. Moreover, in response to infection, mammalian hosts further reduce the availability of metal nutrients by activating epithelial cells and recruiting neutrophils, both of which release metal-binding proteins with antimicrobial function. Microorganisms, in turn, have evolved sophisticated systems to overcome these limitations and acquire the metal ions essential for their growth. Here we review some of the mechanisms employed by the host and by pathogenic microorganisms to compete for transition metal ions, with a discussion of how evading “nutritional immunity” benefits pathogens. Furthermore, we provide new insights on the mechanisms of host-microbe competition for metal ions in the mucosa, particularly in the inflamed gut.

• S100 proteins
• calprotectin
• infection
• iron
• lipocalin-2
• manganese
• nutritional immunity
• zinc

• Activating Transcription Factor 2/metabolism
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Base Sequence
• Binding Sites
• Calcium-Binding Proteins
• Case-Control Studies
• Crohn Disease/genetics
• Crohn Disease/immunology
• Crohn Disease/metabolism
• Cyclic AMP Response Element-Binding Protein/metabolism
• DNA-Binding Proteins
• Epistasis, Genetic
• Female
• Genetic Association Studies
• Genetic Predisposition to Disease
• Humans
• Interleukins/physiology
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic
• Protein Binding
• Receptors, Cell Surface/genetics
• Receptors, Cell Surface/metabolism
• Receptors, Interleukin/genetics
• Sequence Analysis, DNA
• Transcriptional Activation
• Tumor Suppressor Proteins
• Young Adult
• Interleukin-22