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IL-33 promotes GATA-3 polarization of gut-derived T cells in experimental and ulcerative colitis

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Abstract

Background

In the respiratory mucosa, interleukin (IL)-33, has been shown to enhance T helper 2 (TH2)-type responses through the master regulatory gene GATA-3. IL-33 is upregulated in ulcerative colitis (UC), and the aim was to assess if IL-33 holds a similar key position in the shaping of the immune response in experimental colitis (piroxicam-accelerated colitis (PAC) in IL-10 −/− mice, dextran sodium sulfate (DSS) model) and UC.

Methods

Colonic IL-33 expression was determined in UC (8 active UC, 8 quiescent UC, and 7 controls) and experimental colitis. Mesenteric lymph node (MesLN) T cells were isolated from PAC IL-10 −/− mice and stimulated with IL-33.

Results

The colonic IL-33 expression was significantly upregulated all forms of colitis (P < 0.01) and correlated with disease severity score and inflammation (P < 0.001), and with GATA-3 expression levels (P < 0.01); no correlation with the TH1-specific T-bet expression was observed. MesLN T cells stimulated with IL-33 had increased GATA-3 expression, and showed an IL-33 dose-dependent increase in secreted TH2-type cytokines, whereas this effect was abolished by blocking IL-33 signaling. The non-TH2-type cytokine IL-17 was upregulated by IL-33 but in a T cell receptor dependent manner, as opposed to TH2-type cytokines, which required only IL-33 stimulation.

Conclusions

The study demonstrates that intestinal IL-33 is capable of inducing GATA-3 in mucosal T cells, and suggests that IL-33 is a key mediator of pathological TH2 and non-TH2-type responses in intestinal inflammation. Blocking IL-33 signaling could be a feasible option in the treatment of UC.

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Acknowledgments

We thank Anders Hansen, Camilla Frost Sørensen, Hanne Fuglsang, Jeanette Juul, Lotte Friis, and Vibeke Voxen Hansen for excellent technical assistance. This study was supported by grants from Fonden til Lægevidenskabens Fremme (the A. P. Møller Foundation), Novo Nordisk A/S, the Family Erichsen Memorial Foundation, the Lundbeck Foundation, the Axel Muusfeldts Foundation, and the Foundation of Aase and Ejnar Danielsen. JS holds a grant from the Danish Council for Independent Research.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Medical Section 54 O3, Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark

    Jakob Benedict Seidelin, Mehmet Coskun & Ole Haagen Nielsen

  2. Department of Immunopharmacology, Novo Nordisk A/S, Maaloev, Denmark

    Peter Helding Kvist, Thomas Lindebo Holm & Kristine Holgersen

  3. Department of Histology, Novo Nordisk A/S, Maaloev, Denmark

    Peter Helding Kvist, Thomas Lindebo Holm & Kristine Holgersen

  4. Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Kristine Holgersen

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  1. Jakob Benedict Seidelin
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  2. Mehmet Coskun
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  3. Peter Helding Kvist
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  4. Thomas Lindebo Holm
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  6. Ole Haagen Nielsen
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Correspondence to Jakob Benedict Seidelin.

Additional information

J. B. Seidelin and M. Coskun contributed equally to this work.

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Seidelin, J.B., Coskun, M., Kvist, P.H. et al. IL-33 promotes GATA-3 polarization of gut-derived T cells in experimental and ulcerative colitis. J Gastroenterol 50, 180–190 (2015). https://doi.org/10.1007/s00535-014-0982-7

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  • DOI: https://doi.org/10.1007/s00535-014-0982-7

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