Helicobacter pylori Induces Increased Expression of Toll-Like Receptors and Decreased Toll-Interacting Protein in Gastric Mucosa that Persists Throughout Gastric Carcinogenesis

Authors

  • Pedro Pimentel-Nunes,

    Corresponding author
    1. Gastroenterology Department, Portuguese Oncology Institute, Porto, Portugal
    • Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research & Development Unit, Faculty of Medicine, University of Porto, Porto, Portugal
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  • Nádia Gonçalves,

    1. Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research & Development Unit, Faculty of Medicine, University of Porto, Porto, Portugal
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  • Inês Boal-Carvalho,

    1. Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research & Development Unit, Faculty of Medicine, University of Porto, Porto, Portugal
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  • Luís Afonso,

    1. Pathology Department, Portuguese Oncology Institute, Porto, Portugal
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  • Paula Lopes,

    1. Pathology Department, Portuguese Oncology Institute, Porto, Portugal
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  • Roberto Roncon-Albuquerque Jr,

    1. Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research & Development Unit, Faculty of Medicine, University of Porto, Porto, Portugal
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  • Rui Henrique,

    1. Pathology Department, Portuguese Oncology Institute, Porto, Portugal
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  • Luís Moreira-Dias,

    1. Gastroenterology Department, Portuguese Oncology Institute, Porto, Portugal
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  • Adelino F. Leite-Moreira,

    1. Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research & Development Unit, Faculty of Medicine, University of Porto, Porto, Portugal
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  • Mário Dinis-Ribeiro

    1. Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research & Development Unit, Faculty of Medicine, University of Porto, Porto, Portugal
    2. CINTESIS/Department of Biostatistics and Medical Informatics, Porto Faculty of Medicine, Porto, Portugal
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Reprint requests to: Pedro Pimentel-Nunes, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal. E-mail: pedronunesml@gmail.com

Abstract

Background

Toll-like receptors (TLR) are essential for Helicobacter pylori (HP) recognition. Their role in the progression of gastric lesions leading to cancer is not established.

Aim

To evaluate for the first time in humans the expression of TLR2, TLR4, and TLR5, as well as the expression of other related molecules in the entire sequence of gastric lesions.

Methods

Biopsy samples (n = 80, 48% HP+) from normal mucosa, HP gastritis, metaplasia, dysplasia or adenocarcinoma were obtained from 44 patients. mRNA quantification of TLR2, TLR4, TLR5, Toll-interacting protein (TOLLIP), PPAR-γ, NF-κB, TNF-α, COX-1, COX-2, and CDX-2 was performed by real-time RT-PCR. TLR2, TLR4, and TLR5 protein expression was quantified by immunohistochemistry.

Results

When compared to normal mucosa (1.0 arbitrary unit (AU)), HP gastritis presented higher expression of TLR2 (2.23 ± 0.36 AU), TLR4 (1.92 ± 0.40 AU) and TNF-α (2.14 ± 0.50 AU) and lower TOLLIP and PPARγ expression (0.72 ± 0.12 AU, p < .05 all genes). Metaplasia and dysplasia/carcinoma presented higher expression of TLR2 (1.66 ± 0.46 and 1.48 ± 0.20 AU, respectively, p < .05), lower expression of TOLLIP (0.66 ± 0.09 and 0.52 ± 0.04 AU, p < .05) and PPARγ (0.73 ± 0.12 and 0.63 ± 0.10 AU, p < .05). The significant trend for decrease in TOLLIP and PPARγ was associated with increasing levels of CDX-2 from normal mucosa to carcinoma (p < .05), translating that in diffuse and higher TLRs protein expression (p < .05).

Conclusion

Gastric carcinogenesis is associated with decreasing levels of TLRs inhibitors and elevated TLRs levels throughout all the spectrum of lesions. Future studies should investigate if modulation of these receptors activity may influence gastric carcinogenesis and tumor progression.

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