Top

Published in:

01-03-2017 | Original Article—Alimentary Tract

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

Authors: Yoichiro Iboshi, Kazuhiko Nakamura, Keita Fukaura, Tsutomu Iwasa, Haruei Ogino, Yorinobu Sumida, Eikichi Ihara, Hirotada Akiho, Naohiko Harada, Makoto Nakamuta

Published in: Journal of Gastroenterology | Issue 3/2017

Abstract

Background

T helper (T_h) and regulatory T (T_reg) 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 T_h/T_reg-related genes.

Available only for authorised users

Nikolaus S, Schreiber S. Diagnostics of inflammatory bowel disease. Gastroenterology. 2007;133:1670–89.CrossRefPubMed

Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427–34.CrossRefPubMed

Strober W, Fuss IJ. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology. 2011;140:1756–67.CrossRefPubMedPubMedCentral

Fuss IJ, Neurath M, Boirivant M, et al. Disparate CD4 + lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn’s disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996;157:1261–70.PubMed

Fuss IJ, Heller F, Boirivant M, et al. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest. 2004;113:1490–7.CrossRefPubMedPubMedCentral

Heller F, Florian P, Bojarski C, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology. 2005;129:550–64.CrossRefPubMed

Kobori A, Yagi Y, Imaeda H, et al. Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis. J Gastroenterol. 2010;45:999–1007.CrossRefPubMed

Christophi GP, Rong R, Holtzapple PG, et al. Immune markers and differential signaling networks in ulcerative colitis and Crohn’s disease. Inflamm Bowel Dis. 2012;18:2342–56.CrossRefPubMedPubMedCentral

Monteleone G, Biancone L, Marasco R, et al. Interleukin 12 is expressed and actively released by Crohn’s disease intestinal lamina propria mononuclear cells. Gastroenterology. 1997;112:1169–78.CrossRefPubMed

10.

Matsuoka K, Inoue N, Sato T, et al. T-bet upregulation and subsequent interleukin 12 stimulation are essential for induction of Th1 mediated immunopathology in Crohn’s disease. Gut. 2004;53:1303–8.CrossRefPubMedPubMedCentral

11.

Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4 + effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6:1123–32.CrossRefPubMed

12.

Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–41.CrossRefPubMedPubMedCentral

13.

Fujino S, Andoh A, Bamba S, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003;52:65–70.CrossRefPubMedPubMedCentral

14.

Holtta V, Klemetti P, Sipponen T, et al. IL-23/IL-17 immunity as a hall- mark of Crohn’s disease. Inflamm Bowel Dis. 2008;14:1175–84.CrossRefPubMed

15.

Kobayashi T, Okamoto S, Hisamatsu T, et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut. 2008;57:1682–9.CrossRefPubMed

16.

Hölttä V, Klemetti P, Salo HM, et al. Interleukin-17 immunity in pediatric Crohn disease and ulcerative colitis. J Pediatr Gastroenterol Nutr. 2013;57:287–92.CrossRefPubMed

17.

Verma R, Verma N, Paul J. Expression of inflammatory genes in the colon of ulcerative colitis patients varies with activity both at the mRNA and protein level. Eur Cytokine Netw. 2013;24:130–8.PubMed

18.

Öhman L, Dahlén R, Isaksson S, et al. Serum IL-17A in newly diagnosed treatment-naive patients with ulcerative colitis reflects clinical disease severity and predicts the course of disease. Inflamm Bowel Dis. 2013;19:2433–9.CrossRefPubMed

19.

Fransen K, van Sommeren S, Westra H-J, et al. Correlation of genetic risk and messenger RNA expression in a Th17/IL23 pathway analysis in inflammatory bowel disease. Inflamm Bowel Dis. 2014;20:777–82.CrossRefPubMed

20.

Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;8:345–50.CrossRefPubMed

21.

Moran EM, Mullan R, McCormick J, et al. Human rheumatoid arthritis tissue production of IL-17A drives matrix and cartilage degradation: synergy with tumour necrosis factor-alpha, Oncostatin M and response to biologic therapies. Arthritis Res. Ther. 2009;11:R113.CrossRefPubMedPubMedCentral

22.

Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med. 2001;194:629–44.CrossRefPubMedPubMedCentral

23.

Nakamura K, Kitani A, Fuss I, et al. TGF-beta 1 plays an important role in the mechanism of CD4 + CD25 + regulatory T cell activity in both humans and mice. J Immunol. 2004;172:834–42.CrossRefPubMed

24.

Asseman C, Mauze S, Leach MW, Coffman RL, Powrie F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med. 1999;190:995–1004.CrossRefPubMedPubMedCentral

25.

Nalleweg N, Chiriac MT, Podstawa E, et al. IL-9 and its receptor are predominantly involved in the pathogenesis of UC. Gut. 2015;64:743–55.CrossRefPubMed

26.

Raddatz D, Bockemühl M, Ramadori G. Quantitative measurement of cytokine mRNA in inflammatory bowel disease: relation to clinical and endoscopic activity and outcome. Eur J Gastroenterol Hepatol. 2005;17:547–57.CrossRefPubMed

27.

Zahn A, Giese T, Karner M, et al. Transcript levels of different cytokines and chemokines correlate with clinical and endoscopic activity in ulcerative colitis. BMC Gastroenterol. 2009;9:13.CrossRefPubMedPubMedCentral

28.

Tsukada Y, Nakamura T, Iimura M, Iizuka BE, Hayashi N. Cytokine profile in colonic mucosa of ulcerative colitis correlates with disease activity and response to granulocytapheresis. Am J Gastroenterol. 2002;97:2820–8.CrossRefPubMed

29.

Matsuda R, Koide T, Tokoro C, et al. Quantitive cytokine mRNA expression profiles in the colonic mucosa of patients with steroid naive ulcerative colitis during active and quiescent disease. Inflamm Bowel Dis. 2009;15:328–34.CrossRefPubMed

30.

Dziuda DM. Data mining for genomics and proteomics: analysis of gene and protein expression data, vol. 1. New york: John Wiley & Sons; 2010.CrossRef

31.

Karp LC. Heterogeneity of inflammatory bowel diseases. In: Stephan RT, editor. In: Stephan RT, Fergus S, Loren CK, editors. Inflammatory bowel disease: translating basic science into clinical practice. Hoboken: Wiley-Blackwell; 2010.

32.

Iboshi Y, Nakamura K, Ihara E, et al. Multigene analysis unveils distinctive expression profiles of helper T-cell–related genes in the intestinal mucosa that discriminate between ulcerative colitis and Crohn’s disease. Inflamm Bowel Dis. 2014;20(6):967–77.PubMed

33.

Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial. Br Med J. 1989;298(6666):82–6.CrossRef

34.

Hirai F, Matsui T. A critical review of endoscopic indices in ulcerative colitis: inter-observer variation of the endoscopic index. Clin J Gastroenterol. 2008;1:40–5.CrossRefPubMed

35.

Hirai F, Matsui T, Aoyagi K, et al. Validity of activity indices in ulcerative colitis: comparison of clinical and endoscopic indices. Dig Endosc. 2010;22(1):39–44.CrossRefPubMed

36.

Schoepfer AM, Beglinger C, Straumann A, et al. Ulcerative colitis: correlation of the Rachmilewitz endoscopic activity index with fecal calprotectin, clinical activity, C-reactive protein, and blood leukocytes. Inflamm Bowel Dis. 2009;15(12):1851–8.CrossRefPubMed

37.

Florholmen J, Fries W. Candidate mucosal and surrogate biomarkers of inflammatory bowel disease in the era of new technology. Scand J Gastroenterol. 2011;46:1407–17.CrossRefPubMed

38.

Boland BS, Boyle DL, Sandborn WJ, et al. Validated gene expression biomarker analysis for biopsy-based clinical trials in ulcerative colitis. Aliment Pharmacol Ther. 2014;40:477–85.PubMedPubMedCentral

39.

Bogaert S, Laukens D, Peeters H, et al. Differential mucosal expression of Th17-related genes between the inflamed colon and ileum of patients with inflammatory bowel disease. BMC Immunol. 2010;11:61.CrossRefPubMedPubMedCentral

40.

Vandesompele J, De Preter K, Pattyn F, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3:RESEARCH0034.CrossRefPubMedPubMedCentral

41.

Giles MS, Trivigno C. Identity crisis of Th17 cells: many forms, many functions, many questions. Semin Immunol. 2013;25:263–72.CrossRef

42.

Kanai T, Mikami Y, Sujino T, et al. RORγt-dependent IL-17A-producing cells in the pathogenesis of intestinal inflammation. Mucosal Immunol. 2012;5:240–7.CrossRefPubMed

43.

Pappu R, Ramirez-Carrozzi V, Sambandam A. The interleukin 17 cytokine family: critical players in host defence and inflammatory diseases. Immunology. 2011;134(1):8–16.CrossRefPubMedPubMedCentral

44.

Chang SH, Dong C. A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell Res. 2007;17(5):435–40.PubMed

45.

Wright JF, Guo Y, Quazi A, Luxenberg DP, et al. Identification of an interleukin 17F/17A heterodimer in activated human CD4 + T cells. J Biol Chem. 2007;282(18):13447–55.CrossRefPubMed

46.

Hueber W, Sands BE, Lewitzky S, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012;61:1693–700.CrossRefPubMedPubMedCentral

47.

Wedebye Schmidt EG, Larsen HL, Kristensen NN, et al. TH17 cell induction and effects of IL-17A and IL-17F blockade in experimental colitis. Inflamm Bowel Dis. 2013;19(8):1567–76.CrossRefPubMed

48.

Giles DA, Moreno-Fernandez ME, Stankiewicz TE, et al. Regulation of Inflammation by IL-17A and IL-17F Modulates Non-Alcoholic Fatty Liver Disease Pathogenesis. PLoS One. 2016;11:e0149783 Guillou H, editor.CrossRefPubMedPubMedCentral

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
Authors: Yoichiro Iboshi
Kazuhiko Nakamura
Keita Fukaura
Tsutomu Iwasa
Haruei Ogino
Yorinobu Sumida
Eikichi Ihara
Hirotada Akiho
Naohiko Harada
Makoto Nakamuta
Publication date: 01-03-2017
Publisher: Springer Japan
Published in: Journal of Gastroenterology / Issue 3/2017
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI: https://doi.org/10.1007/s00535-016-1221-1

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2017

Novel and highly sensitive immunoassay for total hepatitis B surface antigen, including that complexed with hepatitis B surface antibody

Daclatasvir/asunaprevir/beclabuvir fixed-dose combination in Japanese patients with HCV genotype 1 infection

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

Involvement of herbal medicine as a cause of mesenteric phlebosclerosis: results from a large-scale nationwide survey

Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis

The relationship between HBcrAg and HBV reinfection in HBV related post-liver transplantation patients

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page