title: Increased IL-17A/IL-17F expression ratio represents the key mucosal T helper/regulatory cell-related gene signature paralleling disease activity in ulcerative colitis.
abstract: BACKGROUND
  T helper (Th) and regulatory T (Treg) cell-related cytokines are implicated in inflammatory bowel diseases, including ulcerative colitis (UC). While these cytokines are generally upregulated in inflamed mucosae, the key cytokine profile explaining disease severity has not been determined.
  
  
  METHODS
  The Rachmilewitz endoscopic index (REI) was assessed in 61 UC patients undergoing colonoscopy. Biopsies obtained from inflamed (REI 3-12) and noninflamed (REI 0-2) areas were analyzed by quantitative PCR for expression of mRNAs encoding 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-21, IL-22, IL-23p19, IL-6, and RORC), Th9 (IL-9, IRF4, and PU.1), and Treg (TGF-β and Foxp3). Expression patterns associated with higher REI were determined by univariate and multivariate analyses.
  
  
  RESULTS
  Despite general upregulation, none of these mRNAs showed univariate correlation with REI in inflamed samples. Multiple regression analysis, however, found that joint expression of IL-17A, IL-17F, IL-21, RORC, and TGF-β was significantly predictive of REI (P < 0.0002, R2= 0.380), with major individual contributions by IL-17A (P < 0.0001) and IL-17F (P < 0.0001), which were associated with increased and decreased REI, respectively. Partial correlation analysis, validating this model, indicated differences between IL-17A and IL-17F in correlating with other targets. The IL-17A/IL-17F ratio showed a significant correlation with REI (r = 0.5124, P < 0.0001), whereas no other mRNAs were essentially predictive of REI.
  
  
  CONCLUSIONS
  Mucosal IL-17A/IL-17F ratio significantly correlates with endoscopic score in UC patients, accompanied by their disparate interactions with other Th/Treg-related genes.
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan.|Department of Gastroenterology, Kyushu Medical Center, Clinical Research Center, National Hospital Organization, Fukuoka, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iboshi
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan. knakamur@intmed3.med.kyushu-u.ac.jp.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Fukaura
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Iwasa
authors.affiliation: Department of Gastroenterology, Kitakyushu Municipal Medical Center, Kitakyushu, Japan.
authors.forename: Haruei
authors.initials: H
authors.lastname: Ogino
authors.affiliation: Department of Gastroenterology, Kyushu Medical Center, Clinical Research Center, National Hospital Organization, Fukuoka, Japan.
authors.forename: Yorinobu
authors.initials: Y
authors.lastname: Sumida
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan.
authors.forename: Eikichi
authors.initials: E
authors.lastname: Ihara
authors.affiliation: Department of Gastroenterology, Kitakyushu Municipal Medical Center, Kitakyushu, Japan.
authors.forename: Hirotada
authors.initials: H
authors.lastname: Akiho
authors.affiliation: Department of Gastroenterology, Kyushu Medical Center, Clinical Research Center, National Hospital Organization, Fukuoka, Japan.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Harada
authors.affiliation: Department of Gastroenterology, Kyushu Medical Center, Clinical Research Center, National Hospital Organization, Fukuoka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakamuta
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology*; D003113:Colonoscopy; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics; D007413:Intestinal Mucosa / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012720:Severity of Illness Index; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D015415:Biomarkers; C508717:IL17A protein, human; C440021:IL17F protein, human; D020381:Interleukin-17; D012333:RNA, Messenger
keywords: Endoscopic score; IL-17A/IL-17F ratio; Multigene analysis; T helper subsets; Ulcerative colitis