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IL-33/ST2 axis in inflammation and immunopathology

  • Immunology in Serbia
  • Published:
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Abstract

Interleukin-33 (IL-33), a member of the IL-1 family of cytokines, binds to its plasma membrane receptor, heterodimeric complex consisted of membrane-bound ST2L and IL-1R accessory protein, inducing NFkB and MAPK activation. IL-33 exists as a nuclear precursor and may act as an alarmin, when it is released after cell damage or as negative regulator of NFκB gene transcription, when acts in an intracrine manner. ST2L is expressed on several immune cells: Th2 lymphocytes, NK, NKT and mast cells and on cells of myeloid lineage: monocytes, dendritic cells and granulocytes. IL-33/ST2 axis can promote both Th1 and Th2 immune responses depending on the type of activated cell and microenvironment and cytokine network in damaged tissue. We previously described and discuss here the important role of IL-33/ST2 axis in experimental models of type 1 diabetes, experimental autoimmune encephalomyelitis, fulminant hepatitis and breast cancer. We found that ST2 deletion enhance the development of T cell-mediated autoimmune disorders, EAE and diabetes mellitus type I. Disease development was accompanied by dominantly Th1/Th17 immune response but also higher IL-33 production, which suggest that IL-33 in receptor independent manner could promote the development of inflammatory autoreactive T cells. IL-33/ST2 axis has protective role in Con A hepatitis. ST2-deficient mice had more severe hepatitis with higher influx of inflammatory cells in liver and dominant Th1/Th17 systemic response. Pretreatment of mice with IL-33 prevented Con A-induced liver damage through prevention of apoptosis of hepatocytes and Th2 amplification. Deletion of IL-33/ST2 axis enhances cytotoxicity of NK cells, production of IFN-γ in these cells and systemic production of IFN-γ, IL-17 and TNF-α, which leads to attenuated tumor growth. IL-33 treatment of tumor-bearing mice suppresses activity of NK cells, dendritic cell maturation and enhances alternative activation of macrophages. In conclusion, we observed that IL-33 has attenuated anti-inflammatory effects in T cell-mediated responses and that both IL-33 and ST2 could be further explored as potential therapeutic targets in treatment of immune-mediated diseases.

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Acknowledgments

This study is supported by grants ON175069, ON175071 and ON175103 from Ministry of Education and Science, Republic of Serbia. We thank Dr. Andrew McKenzie for providing us ST2 knockout mice and also thank Milan Milojevic for excellent technical assistance.

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Authors and Affiliations

  1. Faculty of Medicine, Center for Molecular Medicine and Stem Cell Research, University of Kragujevac, Svetozara Markovica 69, 34000, Kragujevac, Serbia

    Marija Milovanovic, Vladislav Volarevic, Gordana Radosavljevic, Ivan Jovanovic, Nada Pejnovic, Nebojsa Arsenijevic & Miodrag L. Lukic

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  1. Marija Milovanovic
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  2. Vladislav Volarevic
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  3. Gordana Radosavljevic
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  4. Ivan Jovanovic
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  5. Nada Pejnovic
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  6. Nebojsa Arsenijevic
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  7. Miodrag L. Lukic
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Correspondence to Miodrag L. Lukic.

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Milovanovic, M., Volarevic, V., Radosavljevic, G. et al. IL-33/ST2 axis in inflammation and immunopathology. Immunol Res 52, 89–99 (2012). https://doi.org/10.1007/s12026-012-8283-9

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  • DOI: https://doi.org/10.1007/s12026-012-8283-9

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