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CLA-supplemented diet accelerates experimental colorectal cancer by inducing TGF-β-producing macrophages and T cells

Mucosal Immunology (2018) | Download Citation

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Abstract

Conjugated linoleic acid (CLA) has been shown to activate the nuclear receptor PPAR-γ and modulate metabolic and immune functions. Despite the worldwide use of CLA dietary supplementation, strong scientific evidence for its proposed beneficial actions are missing. We found that CLA-supplemented diet reduced mucosal damage and inflammatory infiltrate in the dextran sodium sulfate (DSS)-induced colitis model. Conditional deletion of PPAR-γ in macrophages from mice supplemented with CLA diet resulted in loss of this protective effect of CLA, suggesting a PPAR-γ-dependent mechanism mediated by macrophages. However, CLA supplementation significantly worsened colorectal tumor formation induced by azoxymethane and DSS by inducing macrophage and T-cell-producing TGF-β via PPAR-γ activation. Accordingly, either macrophage-specific deletion of PPAR-γ or in vivo neutralization of latency-associated peptide (LAP, a membrane-bound TGF-β)-expressing cells abrogated the protumorigenic effect of CLA. Thus, the anti-inflammatory properties of CLA are associated with prevention of colitis but also with development of colorectal cancer.

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Acknowledgements

We would like to acknowledge Marie Curie fellowship program, and Nuclear Receptor-network EU-funded project for supporting collaboration projects. We are thankful to BASF company for kindly provide Tonalin®, to Dr. Dezső Balázs from Pathology Department from Debrecen University, Hungary for the kind help with pathology discussions and slides manufacture. We are also grateful to Dr. Vany Ferraz from Chemistry Department of UFMG, Brazil for providing CG analysis of CLA diet, to Dr. Denise Carmona (UFMG, Brazil), and Dr. Claudia Martins Carneiro (UFOP, Brazil) for discussion and pathological analysis. This study had financial support from Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil (CNPq) and Fundação de Amparo a Pesquisa do Estado de Minas Gerais, Brazil (FAPEMIG).

Author contributions

T.G.M. designed the project and experiments, carried out the experiments, and wrote the manuscript. L.S.H. set up CAC model and helped perform experiments; A.C.G. helped designed the project and performed experiments; R.P.O. provided input for experiment design; N.M.G.P.Q. performed western blot experiments; D.M. performed epithelial cell-related experiments and qPCR; B.D. helped perform luciferase assays; A.T.V. performed gut permeability; S.L. performed DSS experiment in anti-LAP treatment; M.A.R. performed confocal immunofluorescence microscopy, D.A.G. performed confocal analysis, G.G. designed anti-LAP experiments and provide the antibody; E.F. performed IHC and histology experiments and analysis; H.L.W. provide anti-LAP antibody and reagents, R.M.R. performed experiments and wrote the manuscript. L.N. supervised PPAR-γ experiments, provided LysMCrePPAR-γflox/flox mice, helped design experiments, and corrected manuscript; A.M.C.F. supervised the project, designed experiments, and corrected the manuscript.

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Author notes

    • B Daniel
    •  & L. Nagy

    Present address: Department of Medicine, School of Medicine, Johns Hopkins All Children’s Hospital, Johns Hopkins University, St. Petersburg, FL, 33701, USA

Affiliations

  1. Departamento de Alimentos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Campus Pampulha, 31270-901, Belo Horizonte, MG, Brazil

    • T. G. Moreira
  2. Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

    • T. G. Moreira
    • , L. S. Horta
    • , A. C. Gomes-Santos
    • , R. P. Oliveira
    • , N. M. G. P. Queiroz
    • , A. T. Vieira
    • , A. M. Rodrigues
    • , D. A. Gomes
    •  & A. M. C. Faria
  3. Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    • T. G. Moreira
    • , D. Mangani
    • , S. Liu
    • , G. Gabriely
    • , H. L. Weiner
    •  & R. M. Rezende
  4. Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    • T. G. Moreira
    •  & B Daniel
  5. Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

    • E. Ferreira
  6. Diabetes and Obesity Research Center, Sanford Burnham Medical Research Institute, Lake Nona, Orlando, FL, USA

    • L. Nagy

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The authors declare no competing interests.

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Correspondence to T. G. Moreira or A. M. C. Faria.

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https://doi.org/10.1038/s41385-018-0090-8