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Cytokine Production Is Differentially Modulated in Malignant and Non-malignant Tissues in ST2-Receptor Deficient Mice

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Abstract

IL-33/ST2 axis has been shown to exert both pro- and anti- effects in wound healing and tumor development. To further understand the role of this cytokine complex, we characterized comparatively the inflammatory component of a malignant tissue and non-malignant tissue in mice lacking ST2 receptor (ST2-KO). KO mice and their wild-type (WT) counterparts were either implanted subcutaneously with polyether-polyurethane sponge discs to induce non-malignant fibrovascular tissue growth or inoculated with 4T1 cells to induce mammary tumor. Loss of ST2 receptor in mice resulted in enhanced mammary tumor and fibrovascular tissue relative to the WT animals. The inflammatory parameters (MPO and NAG activities, levels of the cytokines CXCL1/KC, CCL2, TNF-α, TGF-β1, and mast cell number) were differentially modulated in both tissues. In tumors, these parameters were, overall, lower compared with those in tumors of WT mice. In KO implants, CXCL1/KC and TNF-α levels increased; MPO, NAG, and CCL2 levels decreased relative to the WT implants. In addition, deletion of ST2 receptor inhibited mast cell recruitment but had no effect on TGF-β1 levels in implants. Our study has shown antitumorigenic effect of ST2 in mammary tumor and this may be mediated by downregulation of pro-inflammatory cytokines (CXCL1/KC, CCL2, TNF-α, and TGF-β1). Conversely, in the fibrovascular tissue, lack of ST2 receptor resulted in differential modulation of cytokine production. Differential signaling mechanisms may be activated by IL-33/ST2 axis to modulate cytokine production in malignant and non-malignant proliferative processes.

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Acknowledgements

The histological microscopic data shown in this work was obtained using the microscopes and equipment in the Centro de Aquisição e Processamento de Imagens (CAPI-ICB/UFMG). The authors would like to thank Dr. Faria AMC for assistance with reproduction, support, and care of ST2KO animals. Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG-MG/Brazil) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-Brazil) contributed to this study with scholarships.

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Authors and Affiliations

  1. Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Antônio Carlos 6627 – Campus Pampulha, Cx Post 468, Belo Horizonte, MG, CEP 31270-901, Brazil

    Celso Tarso Rodrigues Viana, Laura Alejandra Ariza Orellano, Luciana Xavier Pereira, Simone Aparecida de Almeida, Letícia Chinait Couto, Marcela Guimarães Takahashi de Lazari & Paula Peixoto Campos

  2. Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Antônio Carlos 6627 – Campus Pampulha, Cx Post 468, Belo Horizonte, MG, CEP 31270-901, Brazil

    Silvia Passos Andrade

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  1. Celso Tarso Rodrigues Viana
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Correspondence to Paula Peixoto Campos.

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The use of animals and procedures for this study was approved by the Ethics Committee of Animal Experimentation (CEUA) of Federal University of Minas Gerais, (protocol number 45/2014) and all applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Viana, C.T.R., Orellano, L.A.A., Pereira, L.X. et al. Cytokine Production Is Differentially Modulated in Malignant and Non-malignant Tissues in ST2-Receptor Deficient Mice. Inflammation 41, 2041–2051 (2018). https://doi.org/10.1007/s10753-018-0847-y

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