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1.
Gut ; 58(9): 1207-17, 2009 Sep.
Article in English | MEDLINE | ID: mdl-18483078

ABSTRACT

BACKGROUND AND AIMS: Interleukin 26 (IL-26), a novel IL-10-like cytokine without a murine homologue, is expressed in T helper 1 (Th1) and Th17 cells. Currently, its function in human disease is completely unknown. The aim of this study was to analyse its role in intestinal inflammation. METHODS: Expression studies were performed by reverse transcription-PCR (RT-PCR), quantitative PCR, western blot and immunohistochemistry. Signal transduction was analysed by western blot experiments and ELISA. Cell proliferation was measured by MTS (3-(4,5-dimethylthiazol-2-yl)-5-(carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. IL-26 serum levels were determined by an immunoluminometric assay (ILMA). RESULTS: All examined intestinal epithelial cell (IEC) lines express both IL-26 receptor subunits IL-20R1 and IL-10R2. IL-26 activates extracellular signal-related kinase (ERK)-1/2 and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) mitogen-activated protein (MAP) kinases, Akt and signal transducers and activators of transcription (STAT) 1/3. IL-26 stimulation increases the mRNA expression of proinflammatory cytokines but decreases cell proliferation. In inflamed colonic lesions of patients with Crohn's disease, an elevated IL-26 mRNA expression was found that correlated highly with the IL-8 and IL-22 expression. Immunohistochemical analysis demonstrated IL-26 protein expression in colonic T cells including Th17 cells expressing the orphan nuclear receptor RORgammat, with an increased number of colonic IL-26-expressing cells in active Crohn's disease. CONCLUSION: Intestinal cells express the functional IL-26 receptor complex. IL-26 modulates IEC proliferation and proinflammatory gene expression and its expression is upregulated in active Crohn's disease, indicating a role for this cytokine system in the innate host cell response during intestinal inflammation. For the first time, IL-26 expression is demonstrated in colonic RORgammat-expressing Th17 cells in situ, supporting a role for this cell type in the pathogenesis of Crohn's disease.


Subject(s)
Crohn Disease/immunology , Interleukins/immunology , Intestinal Mucosa/immunology , Signal Transduction/physiology , Adolescent , Adult , Aged , Apoptosis/drug effects , Blotting, Western , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Epithelial Cells/chemistry , Epithelial Cells/immunology , Female , Humans , Immunohistochemistry , Inflammation , Interleukin-17/immunology , Interleukins/genetics , Interleukins/pharmacology , Male , Microscopy, Confocal , Middle Aged , Nuclear Receptor Subfamily 1, Group F, Member 3 , RNA, Messenger/analysis , Receptors, Retinoic Acid/metabolism , Receptors, Thyroid Hormone/metabolism , Reverse Transcriptase Polymerase Chain Reaction/methods , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Young Adult
2.
Tissue Antigens ; 70(3): 238-46, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17661913

ABSTRACT

Recently, a -105G>A promoter polymorphism coding for selenoprotein S (SELS) has been shown to increase proinflammatory cytokine expression. We, therefore, analyzed SELS expression and potential phenotypic consequences of the -105G>A polymorphism in patients with inflammatory bowel disease (IBD). SELS mRNA was measured by quantitative polymerase chain reaction (PCR) in intestinal epithelial cells (IEC) after stimulation with proinflammatory cytokines and in human colonic biopsies of IBD patients as well as in murine models of ileitis and murine cytomegalovirus (MCMV) colitis. Genomic DNA from 563 individuals (Crohn's disease: n = 205; ulcerative colitis: n = 154; controls: n = 204) was analyzed for the presence of the SELS-105G>A polymorphism and the three nucleotide-binding oligomerization domain-containing protein 2 (NOD2)/caspase recruitment domain-containing protein 15 (CARD15) variants p.Arg702Trp, p.Gly908Arg and p.Leu1007fsX1008. SELS mRNA expression was increased in IEC after stimulation with proinflammatory cytokines, while its expression was not significantly altered in murine ileitis and MCMV colitis and in inflamed ileal and colonic lesions in IBD patients compared with normal controls. The SELS-105G>A polymorphism was observed with similar frequencies in IBD patients and controls and was not associated with a certain disease phenotype or serum tumor necrosis factor alpha (TNF-alpha) levels in these patients. Medium serum TNF-alpha was 1.27 pg/ml in IBD patients, while none of the controls had TNF-alpha concentrations above the detection threshold (P < 0.0001). SELS mRNA expression is upregulated by proinflammatory cytokines in IECs but the SELS-105G>A polymorphism is not associated with IBD susceptibility and does not contribute to a certain disease phenotype or increased TNF-alpha levels in IBD patients.


Subject(s)
Gene Expression Regulation/physiology , Genetic Predisposition to Disease , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/pathology , Membrane Proteins/genetics , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Selenoproteins/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Disease Models, Animal , Female , HT29 Cells , Humans , Inflammatory Bowel Diseases/metabolism , Male , Membrane Proteins/biosynthesis , Mice , Mice, Inbred C57BL , Middle Aged , Selenoproteins/biosynthesis , Tumor Necrosis Factor-alpha/metabolism
3.
Aliment Pharmacol Ther ; 25(7): 787-96, 2007 Apr 01.
Article in English | MEDLINE | ID: mdl-17373917

ABSTRACT

AIM: To evaluate the efficacy and safety of adalimumab, a human antitumour necrosis factor-alpha antibody, in induction and maintenance of remission in patients with Crohn's disease either refractory or intolerant to infliximab in a single centre cohort. METHODS: Sixteen Crohn's disease patients received 160 mg adalimumab subcutaneously in week 0, followed by 80 mg every other week. Clinical response was assessed based on Crohn's disease activity index and laboratory parameters (leukocyte count, C-reactive protein). In all patients genotyping for CARD15 variants and the +1059G/C polymorphism in the C-reactive protein gene was performed. RESULTS: In 10 of 16 patients (63%) treated with adalimumab, remission (CDAI score <150) was induced for at least 8 weeks independent of CARD15 or +1059G/C CRP status. In six of these 10 patients ongoing remission is observed now for more than 24 weeks. Adalimumab significantly decreased C-reactive protein serum levels and Crohn's disease activity index. There was one serious complication (fungal pneumonia). Six patients intermittently developed minor dermatological problems resolving after topical therapy. Otherwise, treatment was generally well tolerated. CONCLUSION: Adalimumab can induce and maintain remission in patients with moderate to severe Crohn's disease intolerant or refractory to infliximab. Further experience from larger cohorts is required to evaluate dose regimen and safety profiles in Crohn's disease therapy.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , Antibodies, Monoclonal/administration & dosage , Crohn Disease/drug therapy , Gastrointestinal Agents/administration & dosage , Adalimumab , Administration, Cutaneous , Adult , Aged , Anti-Inflammatory Agents/adverse effects , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Dose-Response Relationship, Drug , Drug Resistance , Female , Gastrointestinal Agents/adverse effects , Humans , Infliximab , Male , Middle Aged , Treatment Outcome
4.
Aliment Pharmacol Ther ; 24(7): 1105-15, 2006 Oct 01.
Article in English | MEDLINE | ID: mdl-16984505

ABSTRACT

BACKGROUND: Serum C-reactive protein (CRP) levels influence the response to anti-tumour necrosis factor (TNF) therapies. AIM: To analyse the influence of the +1059G/C CRP polymorphism on CRP serum levels and disease susceptibility in patients with Crohn's disease (CD). METHODS: Using restriction fragment length polymorphism (RFLP) analysis, genomic DNA from 241 CD patients and 199 unrelated controls was analysed for the +1059G/C substitution in the CRP gene and the common caspase-activation recruitment domain 15 (CARD15) variants. RESULTS: Homozygous C/C carriers were detected only among CD patients (P = 0.066). Patients with ileal involvement (L1 and L3 phenotype) were found in only 58.4% of patients with the wildtype G/G genotype but in 88.2% of the heterozygous G/C carriers (OR 5.26; 95% CI 1.19-23.92) and four of the five C/C homozygous carriers (80%; OR 4.55; 95% CI 1.64-16.67; P = 0.008 for hetero- and homozygous carriers vs. wildtype) which was independent of the presence of CARD15 variants. Increased CD activity was associated with increased CRP serum levels (P < 0.005). For Crohn's disease activity index (CDAI) < 150, C/C homozygosity for the +1059 G/C polymorphism was associated with significantly lower CRP serum levels (P < 0.01). CONCLUSIONS: The C allele of the CRP +1059G/C polymorphism is associated with decreased serum CRP levels and increased likelihood of disease involvement of the terminal ileum in CD patients.


Subject(s)
C-Reactive Protein/metabolism , Crohn Disease/genetics , Crohn Disease/metabolism , Ileum/metabolism , Tumor Necrosis Factor-alpha/genetics , Adult , C-Reactive Protein/genetics , Crohn Disease/blood , Female , Humans , Male , Middle Aged , Polymorphism, Genetic
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