Helicobacter pylori induces increased expression of Toll-like receptors and decreased Toll-interacting protein in gastric mucosa that persists throughout gastric carcinogenesis.
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.


OBJECTIVE
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).


CONCLUSIONS
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.
Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal. pedronunesml@gmail.com
Pedro
P
Pimentel-Nunes
Nádia
N
Gonçalves
Inês
I
Boal-Carvalho
Luís
L
Afonso
Paula
P
Lopes
Roberto
R
Roncon-Albuquerque
Rui
R
Henrique
Luís
L
Moreira-Dias
Adelino F
AF
Leite-Moreira
Mário
M
Dinis-Ribeiro
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D003430:Cross-Sectional Studies; D005260:Female; D005753:Gastric Mucosa / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D020869:Gene Expression Profiling; D016481:Helicobacter Infections / Q000150:complications / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D016480:Helicobacter pylori / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051193:Toll-Like Receptors / Q000096:biosynthesis* / Q000276:immunology
D047908:Intracellular Signaling Peptides and Proteins; C410602:TOLLIP protein, human; D051193:Toll-Like Receptors