Intestinal IL17F gene expression is increased in active CD. The IL17F p.His161Arg polymorphism is not associated with IBD susceptibility and has no epistatic interaction with CD-associated IL23R variants.

BackgroundThe IL23R gene has been identified as a susceptibility gene for inflammatory bowel disease (IBD) in the North American population. The aim of our study was to test this association in a large German IBD cohort and to elucidate potential interactions with other IBD genes as well as phenotypic consequences of IL23R variants.MethodsGenomic DNA from 2670 Caucasian individuals including 833 patients with Crohn's disease (CD), 456 patients with ulcerative colitis (UC), and 1381 healthy unrelated controls was analyzed for 10 IL23R SNPs. Genotyping included the NOD2 variants p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008 and polymorphisms in SLC22A4/OCTN1 (1672 C→T) and SLC22A5/OCTN2 (–207 G→C).ResultsAll IL23R gene variants analyzed displayed highly significant associations with CD. The strongest association was found for the SNP rs1004819 [P = 1.92×10−11; OR 1.56; 95 % CI (1.37–1.78)]. 93.2% of the rs1004819 TT homozygous carriers as compared to 78% of CC wildtype carriers had ileal involvement [P = 0.004; OR 4.24; CI (1.46–12.34)]. The coding SNP rs11209026 (p.Arg381Gln) was protective for CD [P = 8.04×10−8; OR 0.43; CI (0.31–0.59)]. Similar, but weaker associations were found in UC. There was no evidence for epistasis between the IL23R gene and the CD susceptibility genes CARD15 and SLC22A4/5.Conclusion IL23R is an IBD susceptibility gene, but has no epistatic interaction with CARD15 and SLC22A4/5. rs1004819 is the major IL23R variant associated with CD in the German population, while the p.Arg381Gln IL23R variant is a protective marker for CD and UC.

The Th17 cytokine IL-22 is expressed at high levels in CD and correlates with disease activity, offering a better separation between active and inactive CD than IL-6 and TNF-alpha. IL23R genotypes influence IL-22 serum expression, linking genetic CD susceptibility to Th17 cell function for the first time.

ATG16L1 is a CD susceptibility gene without epistatic interaction with other CD susceptibility genes and is not upregulated in intestinal inflammation.

Resistin levels are an independent predictor of disease activity in patients with CD. Resistin may represent a novel link between inflammation and IBD.

The TLR4 Asp299Gly polymorphism is a risk factor for CD. TLR4 and CARD15/NOD2 mutations may contribute to distinct disease phenotypes.

The expression of the chemokine fractalkine is upregulated by proinflammatory cytokines and enhanced in inflamed CD lesions. The CX3CR1 T280M polymorphism appears to influence CD phenotype and localization.

The gut is home to a large number of Treg, with both CD4 1 CD25 1 Treg and bacterial antigen-specific Tr1 cells present in normal mouse intestinal lamina propria. It has been shown recently that intestinal mucosal DC are able to induce Foxp3 1 Treg through production of TGF-b plus retinoic acid (RA). However, the factors instructing DC toward this mucosal phenotype are currently unknown. Curcumin has been shown to possess a number of biologic activities including the inhibition of NF-jB signaling. We asked whether curcumin could modulate DC to be tolerogenic whose function could mimic mucosal DC. We report here that curcumin modulated BM-derived DC to express ALDH1a and IL-10. These curcumin-treated DC induced differentiation of naïve CD4 1 T cells into Treg resembling Treg in the intestine, including both CD4 1 CD25 1 Foxp3 1 Treg and IL-10-producing Tr1 cells. Such Treg induction required IL-10, TGF-b and retinoic acid produced by curcumin-modulated DC. Cell contact as well as IL-10 and TGF-b production were involved in the function of such induced Treg. More importantly, these Treg inhibited antigen-specific T-cell activation in vitro and inhibited colitis due to antigen-specific pathogenic T cells in vivo.