ABSTRACT
Interleukin (IL)-17C is a novel member of the IL-17 cytokine family. Its function in human inflammatory bowel disease (IBD) remains elusive as its role in colonic inflammation is entirely derived from murine models. We aimed to analyze the role of IL-17C in human IBD, focusing on T helper type 17 (Th17) cell- and intestinal epithelial cell (IEC)-dependent mechanisms. IL-17C mRNA (P=0.005), serum levels (P=0.008), and colonic staining intensity (P=0.004) is increased in active IBD. Serum IL-17C levels are modified by IL23R genotypes and IL-17C mRNA correlates (r>0.5, P<0.001) with IL-17A, tumor necrosis factor (TNF)-α, C-C motif chemokine ligand 20 (CCL20) and IL-23 mRNA in the inflamed colon of IBD patients. In the inflamed colon, IL-17C is produced by enteroendocrine and goblet cells, with contrary polar cytosolic localization of IL-17C within the cellular axis. In these two cell types, IL-17A strongly amplifies TNF-α-induced IL-17C production. On the molecular level, IL-17C production in IECs is dependent on TNF-α-activated nuclear factor-κB, extracellular signal-regulated kinase-1/2 and p38, and IL-17A-activated Akt, monocyte chemotactic protein-induced protein 1, and C/EBPδ. IL-17C upregulates the Th17 chemoattractant CCL20 in IECs. In summary, our findings support the involvement of IL-17A-amplified IL-17C production by enteroendocrine and goblet cells in the pathogenesis of active IBD, revealing an interaction between the neuroendocrine system and the Th17 pathway in human IBD.
Subject(s)
Epithelial Cells/metabolism , Goblet Cells/metabolism , Inflammatory Bowel Diseases/metabolism , Interleukin-17/metabolism , Neuroendocrine Cells/metabolism , Autocrine Communication , Biomarkers , CCAAT-Enhancer-Binding Proteins/metabolism , Chromogranin A/metabolism , Connexin 43/metabolism , Cytokines/genetics , Cytokines/metabolism , Gene Expression , Genotype , Humans , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/pathology , Interleukin-17/blood , Interleukin-17/genetics , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Peptide Fragments/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA Stability , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Interleukin/genetics , Receptors, Interleukin/metabolism , Ribonucleases/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism , Transcription Factors/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: Recent studies suggest a role for the endocannabinoid system, including fatty acid amide hydrolase (FAAH), in intestinal inflammation. AIM: To analyse FAAH expression and the FAAH 385 C/A (p.Pro129Thr; rs324420) single nucleotide polymorphism (SNP) in-patients with Crohn's disease (CD) and ulcerative colitis (UC). PATIENTS AND METHODS: Genomic DNA from 1008 individuals (CD: n = 435; UC: n = 167; controls: n = 406) was analysed for the FAAH 385 C/A SNP. We determined FAAH mRNA expression by quantitative PCR in CD and UC lesions as well as in intestinal epithelial cells (IECs). RESULTS: There were no significant differences regarding the frequency of this SNP in the three study groups (CD, UC, controls). However, CD patients homozygous for the FAAH p.Pro129Thr polymorphism were more likely to develop a severe disease phenotype associated with fistulas (P = 0.03, OR 3.12, 95% CI 1.08-8.98) and extra-intestinal manifestations (P = 0.005, OR 4.29, CI 1.49-12.35). In UC, homozygous carriers had an earlier disease onset than wild-type carriers (P = 0.01). FAAH mRNA expression correlated with IL-8 mRNA expression in CD lesions (r = 0.53). However, pro-inflammatory stimuli did not significantly increase FAAH mRNA expression in IECs. CONCLUSION: The FAAH p.Pro129Thr polymorphism may modulate the CD phenotype.
