Increased IL-17A/IL-17F expression ratio represents the key mucosal T helper/regulatory cell-related gene signature paralleling disease activity in ulcerative colitis

Yoichiro Iboshi, Kazuhiko Nakamura, Keita Fukaura, tsutomu iwasa, Haruei Ogino, Yorinobu Sumida, Eikichi Ihara, Hirotada Akiho, Naohiko Harada, Makoto Nakamuta

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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.

Original languageEnglish
Pages (from-to)315-326
Number of pages12
JournalJournal of gastroenterology
Volume52
Issue number3
DOIs
Publication statusPublished - Mar 1 2017

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Interleukin-17
Regulatory T-Lymphocytes
Helper-Inducer T-Lymphocytes
Ulcerative Colitis
Genes
Cytokines
Messenger RNA
Interleukin-23 Subunit p19
Interleukin-12 Subunit p35
Interleukin-9
Interleukin-12 Subunit p40
Interleukin-13
Colonoscopy
Inflammatory Bowel Diseases
Interleukin-4
Interleukin-6
Mucous Membrane
Transcription Factors
Up-Regulation
Multivariate Analysis

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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Increased IL-17A/IL-17F expression ratio represents the key mucosal T helper/regulatory cell-related gene signature paralleling disease activity in ulcerative colitis. / Iboshi, Yoichiro; Nakamura, Kazuhiko; Fukaura, Keita; iwasa, tsutomu; Ogino, Haruei; Sumida, Yorinobu; Ihara, Eikichi; Akiho, Hirotada; Harada, Naohiko; Nakamuta, Makoto.

In: Journal of gastroenterology, Vol. 52, No. 3, 01.03.2017, p. 315-326.

Research output: Contribution to journalArticle

Iboshi, Yoichiro ; Nakamura, Kazuhiko ; Fukaura, Keita ; iwasa, tsutomu ; Ogino, Haruei ; Sumida, Yorinobu ; Ihara, Eikichi ; Akiho, Hirotada ; Harada, Naohiko ; Nakamuta, Makoto. / Increased IL-17A/IL-17F expression ratio represents the key mucosal T helper/regulatory cell-related gene signature paralleling disease activity in ulcerative colitis. In: Journal of gastroenterology. 2017 ; Vol. 52, No. 3. pp. 315-326.
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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.",
author = "Yoichiro Iboshi and Kazuhiko Nakamura and Keita Fukaura and tsutomu iwasa and Haruei Ogino and Yorinobu Sumida and Eikichi Ihara and Hirotada Akiho and Naohiko Harada and Makoto Nakamuta",
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AU - Iboshi, Yoichiro

AU - Nakamura, Kazuhiko

AU - Fukaura, Keita

AU - iwasa, tsutomu

AU - Ogino, Haruei

AU - Sumida, Yorinobu

AU - Ihara, Eikichi

AU - Akiho, Hirotada

AU - Harada, Naohiko

AU - Nakamuta, Makoto

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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.

AB - 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.

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