Linking genetic susceptibility to Crohn's disease with Th17 cell function:: IL-22 serum levels are increased in Crohn's disease and correlate with disease activity and IL23R genotype status

Background: We analyzed the influence of Crohn's disease (CD)associated IL23R gene variants on IL-22 that is expressed in IL23R+ Th17 cells. Methods: IL-22 serum levels were measured in 242 CD patients and in 31 healthy controls. Subanalyses included serum levels of IL-6, TNF-alpha, IL-17A, IL-17F, C-reactive protein (CRP), and leukocyte count. In all patients, genotyping for 10 CD-associated IL23R single nucleotide polymorphisms (SNPs) and the 3 main CD-associated CARD15 variants was performed. Results: There was a highly significant increase in IL-22 serum expression in CD patients compared to healthy controls (P = 2.53 X 10(-9)). IL-22 serum levels correlated with disease activity: IL-22 levels in patients with a Crohn's disease activity index (CDAI) > 150 were significantly higher than in patients with a CDAI < 150 (P = 0.001), while TNF-alpha and IL-6 were not significantly different between these 2 groups. Analyzing the effect of 10 IL23R variants on IL-22 serum levels, we demonstrated that the quotients of mean IL-22 serum levels of carriers of the minor allele to the mean serum IL-22 in wildtype carriers correlated highly with the corresponding CD susceptibility risk for each gene variant (r = 0.807). The IL-22 levels in carriers of CD risk-increasing IL23R variants were significantly higher than in carriers of CD risk-decreasing IL23R variants (P = 0.008). Conclusions: 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.