Skip to main content

Advertisement

SpringerLink
Log in

Interleukin-19 contributes as a protective factor in experimental Th2-mediated colitis

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Inflammatory bowel disease results from chronic dysregulation of the mucosal immune system and aberrant activation of both the innate and adaptive immune responses. IL-19 is a member of the IL-10 family, and IL-10 plays an important role in inflammatory bowel disease. We have previously shown that IL-19 knockout mice are more susceptible to innate-mediated colitis. Next, we ask whether IL-19 contributes to T cells-mediated colitis. Here, we investigated the role of IL-19 in a mouse model of Th2 cell-mediated colitis. Inflammatory responses in IL-19-deficient mice were assessed using a Th2-mediated colitis induced by oxazolone. The colitis was evaluated by analyzing the body weight loss and histology of the colon. Lymph node cells were cultured in vitro to determine cytokine production. IL-19 knockout mice exacerbated oxazolone-induced colitis by stimulating the transport of inflammatory cells into the colon, and by increasing IgE production and the number of circulating eosinophil. The exacerbation of oxazolone-induced colonic inflammation following IL-19 knockout mice was accompanied by an increased production of IL-4 and IL-9, but no changes in the expression of IL-5 and IL-13 in lymph node cells. IL-19 plays an anti-inflammatory role in the Th2-mediated colitis model, suggesting that IL-19 may represent a potential therapeutic target for reducing colonic inflammation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

CD:

Crohn’s disease

DSS:

dextran sulfate sodium

HE:

hematoxylin and eosin

IBDs:

inflammatory bowel diseases

IFN:

interferon

KO:

IL-19-knockout

MPO:

myeloperoxidase

UC:

ulcerative colitis

References

  • Azuma YT, Hagi K, Shintani N, Kuwamura M, Nakajima H, Hashimoto H, Baba A, Takeuchi T (2008) PACAP provides colonic protection against dextran sodium sulfate induced colitis. J Cell Physiol 216:111–119

    Article  CAS  PubMed  Google Scholar 

  • Azuma YT, Matsuo Y, Kuwamura M, Yancopoulos GD, Valenzuela DM, Murphy AJ, Nakajima H, Karow M, Takeuchi T (2010a) Interleukin-19 protects mice from innate-mediated colonic inflammation. Inflamm Bowel Dis 16:1017–1028

    Article  PubMed  Google Scholar 

  • Azuma YT, Nishiyama K, Matsuo Y, Kuwamura M, Morioka A, Nakajima H, Takeuchi T (2010b) PPARα contributes to colonic protection in mice with DSS-induced colitis. Int Immunopharmacol 10:1261–1267

    Article  CAS  PubMed  Google Scholar 

  • Boirivant M, Fuss IJ, Chu A, Strober W (1998) Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4. J Exp Med 188:1929–1939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bouma G, Strober W (2003) The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol 3:521–533

    Article  CAS  PubMed  Google Scholar 

  • Camelo A, Barlow JL, Drynan LF, Neill DR, Ballantyne SJ, Wong SH, Pannell R, Gao W, Wrigley K, Sprenkle J, McKenzie AN (2012) Blocking IL-25 signalling protects against gut inflammation in a type-2 model of colitis by suppressing nuocyte and NKT derived IL-13. J Gastoenterol 47:1198–1211

    Article  CAS  Google Scholar 

  • Cote-Sierra J, Foucras G, Guo L, Chiodetti L, Young HA, Hu-Li J, Zhu J, Paul WE (2004) Interleukin 2 plays a central role in Th2 differentiation. Proc Natl Acad Sci U S A 101:3880–3885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dieleman LA, Ridwan BU, Tennyson GS, Beagley KW, Bucy RP, Elson CO (1994) Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. Gastroenterology 107:1643–1652

    Article  CAS  PubMed  Google Scholar 

  • Fiocchi C (1998) Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 115:182–205

    Article  CAS  PubMed  Google Scholar 

  • Fonseca-Camarillo G, Furuzawa-Carballeda J, Granados J, Yamamoto-Furusho JK (2014) Expression of interleukin (IL)-19 and IL-24 in inflammatory bowel disease patients: a cross-sectional study. Clin Exp Immunol 177:64–75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fuss IJ, Marth T, Neurath MF, Pearlstein GR, Jain A, Strober W (1999) Anti-interleukin 12 treatment regulates apoptosis of Th1 cells in experimental colitis in mice. Gastroenterology 117:1078–1088

    Article  CAS  PubMed  Google Scholar 

  • Gallagher G, Dickensheets H, Eskdale J, Izotova LS, Mirochnitchenko OV, Peat JD, Vazquez N, Pestka S, Donnelly RP, Kotenko SV (2000) Cloning, expression and initial characterization of interleukin-19 (IL-19), a novel homologue of human interleukin-10 (IL-10). Genes Immun 1:442–450

    Article  CAS  PubMed  Google Scholar 

  • Gerlach K, Hwang Y, Nikolaev A, Atreya R, Dornhoff H, Steiner S, Lehr HA, Wirtz S, Vieth M, Waisman A, Rosenbauer F, McKenzie AN, Weigmann B, Neurath MF (2014) TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat Immunol 15:676–686

    Article  CAS  PubMed  Google Scholar 

  • Habtezion A, Toivola DM, Butcher EC, Omary MB (2005) Keratin-8-deficient mice develop chronic spontaneous Th2 colitis amenable to antibiotic treatment. J Cell Sci 118:1971–1980

    Article  CAS  PubMed  Google Scholar 

  • Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, Mankertz J, Gitter AH, Bürgel N, Fromm M, Zeitz M, Fuss I, Strober W, Schulzke JD (2005) Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129:550–564

    Article  CAS  PubMed  Google Scholar 

  • Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W (2002) Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17:629–638

    Article  CAS  PubMed  Google Scholar 

  • Hoving JC, Kirstein F, Nieuwenhuizen NE, Fick LC, Hobeika E, Reth M, Brombacher F (2012) B cells that produce immunoglobulin E mediate colitis in BALB/c mice. Gastroenterology 142:96–108

    Article  CAS  PubMed  Google Scholar 

  • Inoue S, Matsumoto T, Iida M, Mizuno M, Kuroki F, Hoshika K, Shimizu M (1999) Characterization of cytokine expression in the rectal mucosa of ulcerative colitis: correlation with disease activity. Am J Gastroenterol 94:2441–2446

    Article  CAS  PubMed  Google Scholar 

  • Kitani A, Fuss IJ, Nakamura K, Schwartz OM, Usui T, Strober W (2000) Treatment of experimental (trinitrobenzene sulfonic acid) colitis by intranasal administration of transforming growth factor (TGF)-beta1 plasmid: TGF-beta1-mediated suppression of T helper cell type 1 response occurs by interleukin (IL)-10 induction and IL-12 receptor beta2 chain downregulation. J Exp Med 192:41–52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kojouharoff G, Hans W, Obermeier F, Männel DN, Andus T, Schölmerich J, Gross V, Falk W (1997) Neutralization of tumour necrosis factor (TNF) but not of IL-1 reduces inflammation in chronic dextran sulphate sodium-induced colitis in mice. Clin Exp Immunol 107:353–358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuo Y, Azuma YT, Kuwamura M, Kuramoto N, Nishiyama K, Yoshida N, Ikeda Y, Fujimoto Y, Nakajima H, Takeuchi T (2015) Interleukin 19 reduces inflammation in chemically induced experimental colitis. Int Immunopharmacol 29:468–475

    Article  CAS  PubMed  Google Scholar 

  • Monteleone G, Monteleone I, Fina D, Vavassori P, Del Vecchio BG, Caruso R, Tersigni R, Alessandroni L, Biancone L, Naccari GC, MacDonald TT, Pallone F (2005) Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn’s disease. Gastroenterology 128:687–694

    Article  CAS  PubMed  Google Scholar 

  • Naito Y, Takagi T, Handa O, Ishikawa T, Nakagawa S, Yamaguchi T, Yoshida N, Minami M, Kita M, Imanishi J, Yoshikawa T (2003) Enhanced intestinal inflammation induced by dextran sulfate sodium in tumor necrosis factor-alpha deficient mice. J Gastroenterol Hepatol 18:560–569

    Article  CAS  PubMed  Google Scholar 

  • Naito Y, Takagi T, Uchiyama K, Kuroda M, Kokura S, Ichikawa H, Yanagisawa R, Inoue K, Takano H, Satoh M, Yoshida N, Okanoue T, Yoshikawa T (2004) Reduced intestinal inflammation induced by dextran sodium sulfate in interleukin-6-deficient mice. Int J Mol Med 14:191–196

    CAS  PubMed  Google Scholar 

  • Sabat R, Wallace E, Endesfelder S, Wolk K (2007) IL-19 and IL-20: two novel cytokines with importance in inflammatory diseases. Expert Opin Ther Targets 11:601–612

    Article  CAS  PubMed  Google Scholar 

  • Siegmund B, Lehr HA, Fantuzzi G, Dinarello CA (2001) IL-1beta -converting enzyme (caspase-1) in intestinal inflammation. Proc Natl Acad Sci U S A 98:13249–13254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sitkauskiene B, Johansson AK, Sergejeva S, Lundin S, Sjöstrand M, Lötvall J (2004) Regulation of bone marrow and airway CD34+ eosinophils by interleukin-5. Am J respire Cell Mol Biol 30:367–378

    Article  CAS  Google Scholar 

  • Tanaka J, Saga K, Kido M, Nishiura H, Akamatsu T, Chiba T, Watanabe N (2010) Proinflammatory Th2 cytokines induce production of thymic stromal lymphopoietin in human colonic epithelial cells. Dig Dis Sci 55:1896–1904

    Article  CAS  PubMed  Google Scholar 

  • Tong M, Li X, Wegener Parfrey L, Roth B, Ippoliti A, Wei B, Borneman J, McGovern DP, Frank DN, Li E, Horvath S, Knight R, Braun J (2013) A modular organization of the human intestinal mucosal microbiota and its association with inflammatory bowel disease. PLoS One 8:e80702

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhu J, Wang Y, Yang F, Sang L, Zhai J, Li S, Li Y, Wang D, Lu C, Sun X (2015) IL-33 alleviates DSS-induced chronic colitis in C57BL/6 mice colon lamina propria by suppressing Th17 cell response as well as Th1 cell response. Int Immunopharmacol 29:846–853

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Grants-in-Aid for Young Scientists (B) 20780209 (Y.T.A.) and 23780300 (Y.T.A.) and was supported by Grant-in-Aid for Scientific Research (B) 25292174 (Y.T.A.).

Author information

Authors and Affiliations

  1. Laboratory of Veterinary Pharmacology, Division of Veterinary Science, Osaka Prefecture University Graduate School of Life and Environmental Science, Izumisano, 598-8531, Japan

    Yasuyuki Fujimoto, Yasu-Taka Azuma, Yukiko Matsuo, Mariko Miki, Naoki Azuma, Midori Teramoto, Kazuhiro Nishiyama, Hidemitsu Nakajima & Tadayoshi Takeuchi

  2. Laboratory of Veterinary Pathology, Division of Veterinary Science, Osaka Prefecture University Graduate School of Life and Environmental Science, Izumisano, 598-8531, Japan

    Mitsuru Kuwamura & Takeshi Izawa

  3. Laboratory of Molecular Pharmacology, Setsunan University Faculty of Pharmaceutical Sciences, Hirakata, 573-0101, Japan

    Nobuyuki Kuramoto

Authors
  1. Yasuyuki Fujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yasu-Taka Azuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yukiko Matsuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mitsuru Kuwamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nobuyuki Kuramoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mariko Miki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Naoki Azuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Midori Teramoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kazuhiro Nishiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Takeshi Izawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hidemitsu Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tadayoshi Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasu-Taka Azuma.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fujimoto, Y., Azuma, YT., Matsuo, Y. et al. Interleukin-19 contributes as a protective factor in experimental Th2-mediated colitis. Naunyn-Schmiedeberg's Arch Pharmacol 390, 261–268 (2017). https://doi.org/10.1007/s00210-016-1329-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-016-1329-0

Keywords

Search

Navigation