Key Mucosal Helper T Cell-Related Gene Signature Paralleling Disease Activity in Ulcerative Colitis Is Underlain by Different Interactions Between IL-17A and IL-17F With Other Helper T Cell-Related Genes

Abstract

Introduction: T helper (Th) and T regulatory (Treg) cell-related cytokines are involved in the pathogenesis of inflammatory bowel diseases, such as ulcerative colitis (UC). However, in inflamed mucosae these molecules seem to be upregulated almost unselectively, and thus predominant molecules contributing to the aberrant immune response and disease activity in UC is undetermined. Methods: Forty-seven UC patients undergoing colonoscopy were assessed with Rachmilewitz endoscopic index (REI, 0-12), which scores mucosal damage. Biopsies obtained from inflamed (REI=3-12) and noninflamed (REI=0-2) area were analysed for mRNA expression of cytokines and transcription factors related to Th1 (TNF-α, IFN-γ, IL-12p35, IL- 12p40, and T-bet), Th2 (IL-4, IL-13, IL-33, and GATA3), Th17 (IL-17A, IL-17F, IL-23p19, IL-21, IL-22, IL-6, and RORC) and Treg (TGF-β and Foxp3) by quantitative PCR. Their expression pattern paralleling higher REI was sought by univariate and multivariate analyses. Results: No target expression univariately correlated with REI in inflamed samples despite their general upregulation. Multiple regression analysis, however, identified a significant REI-predictive model (P=0.0011, RSq=0.472), consisting of IL-17A, IL-17F, IL-21, IL-22, RORC, and Foxp3 levels, with major individual contribution of IL-17A (P=0.0001) and IL-17F (P < 0.0001), which shifted REI upward and downward, respectively. Partial correlation analysis validated this result and further indicated some differeces in correlations between IL-17A and IL-17F with other targets when influences of al the other targets levels were taken into account. Ultimately, simply IL-17A/IL-17F ratio, correlated with REI substantially(r=0.5120, P=0.0007), whereas levels of IL-13, IFN-γ, TNF-α and etc. did not essentially serve as significant parameters in REI-predictive models. Conclusion: Mucosal IL-17A/IL-17F ratio significantly correlated with endoscopic score in UC, indicating different roles of IL-17A and IL-17F in the immune response. Their disparate interactions with other Th/Treg-related genes underlying this finding were elucidated through untangling the complex correlations among simultaneously upregulated genes. Predominant roles of Th17 cytokines over IL-13 or Th1 cytokines in the pathophysiology of UC were also suggested from the present study.