Profiles of gene polymorphisms in cytokines and toll-like receptors with higher risk for gastric cancer

Background: Chronic inflammation and gastric carcinogenesis show a close association, so gene polymorphisms that modify the intensity of the inflammatory response may contribute to variations in gastric cancer risk. Aims: The purpose of this study was to investigate the combined effect of the pro- and anti-inflammatory cytokines and toll-like receptors polymorphisms on the chronic gastritis and gastric cancer risk in a Brazilian population sample. Methods: We evaluated 669 DNA samples (200 of gastric cancer [GC], 229 of chronic gastritis [CG], and 240 of healthy individuals [C]). Ten polymorphisms were genotyped: IL-1RN and TLR2 -196 to -174 del using the allele-specific PCR method and TNF-A (rs1800629; rs1799724), TNF-B (rs909253), IL-8 (rs4073; rs2227532), IL-10 (rs1800872) and TLR4 (rs4986790; rs4986791) using PCR-RFLP. Results: Polymorphisms TNF-A-308G/A, IL-8-251A/T, TNF-B + 252A/G and TLR4 + 1196C/T were not associated with risk of any gastric lesion. However, an association with increased risk for GC was observed for polymorphisms IL-1RNL/2 (p < 0.001), TNF-A-857C/T (p = 0.022), IL-8-845T/C (p < 0.001), IL-10-592C/A (p < 0.001), TLR2ins/del (p < 0.001), and TLR4 + 896A/G (p = 0.033). In CG, an association was observed only with polymorphisms IL-1RNL/2 and IL-10-592A/C (p < 0.001 for both). A combined analysis of these six polymorphisms associated with GC revealed a profile with two to four combined genotypes which confer a higher risk of gastric carcinogenesis, with an OR increased 2.95-fold to 50.4-fold, highlighting the combinations IL-1RN2/TNF-A-857T/IL-8-845C, IL-1RN2/IL-8-845C/TLR2del, IL-1RN2/IL-10-592A/TLR4 + 896G, IL-10-592A/TLR2del/ TLR4 + 896G, and IL-1RN2/TNFA-857T/IL8-845C/TLR2del. Conclusions: Our findings evidenced that the combined effect of polymorphisms in genes involved in the inflammatory process may potentiate the risk of gastric cancer, thus emphasizing the importance of evaluating multiple polymorphisms together. © 2012 Springer Science+Business Media New York.

Toll-like receptor 2 knockdown modulates interleukin (IL)-6 and IL-8 but not stromal derived factor-1 (SDF-1/CXCL12) in human periodontal ligament and gingival fibroblasts

Background: Fibroblasts are now seen as active components of the immune response because these cells express Toll-like receptors (TLRs), recognize pathogen-associated molecular patterns, and mediate the production of cytokines and chemokines during inflammation. The innate host response to lipopolysaccharide (LPS) from Porphyromonas gingivalis is unusual inasmuch as different studies have reported that it can be an agonist for Toll-like receptor 2 (TLR2) and an antagonist or agonist for Toll-like receptor 4 (TLR4). This study investigates and compares whether signaling through TLR2 or TLR4 could affect the secretion of interleukin (IL)-6, IL-8, and stromal derived factor-1 (SDF-1/CXCL12) in both human gingival fibroblasts (HGF) and human periodontal ligament fibroblasts (HPDLF). Methods: After small interfering RNA-mediated silencing of TLR2 and TLR4, HGF and HPDLF from the same donors were stimulated with P. gingivalis LPS or with two synthetic ligands of TLR2, Pam2CSK4 and Pam3CSK4, for 6 hours. IL-6, IL-8, and CXCL12mRNA expression and protein secretion were evaluated by quantitative polymerase chain reaction and enzymelinked immunosorbent assay, respectively. Results: TLR2 mRNA expression was upregulated in HGF but not in HPDLF by all the stimuli applied. Knockdown of TLR2 decreased IL-6 and IL-8 in response to P. gingivalis LPS, or Pam2CSK4 and Pam3CSK4, in a similar manner in both fibroblasts subpopulations. Conversely, CXCL12 remained unchanged by TLR2 or TLR4 silencing. Conclusion: These results suggest that signaling through TLR2 by gingival and periodontal ligament fibroblasts can control the secretion of IL-6 and IL-8, which contribute to periodontal pathogenesis, but do not interfere with CXCL12 levels, an important chemokine in the repair process.

Evaluation of Toll-Like Receptor 2 and 4 RNA Expression and the Cytokine Profile in Postmenopausal Women with Metabolic Syndrome

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

O papel da proteína TET2 no enriquecimento do DNA genômico em 5-hidroximetilcitosina em lesões elanocíticas pré-malignas e pré-metastáticas com fenótipo stem cell-like

Durante a transformação maligna dos melanócitos, padrões de metilação do DNA encontram-se alterados, afetando a expressão gênica. As citosinas metiladas (5mC) podem ser hidroxiladas pelas dioxigenases dependentes de 2-oxoglutarato e Fe(II), Tet1, 2 e 3, resultando na formação de 5-hidroximetilcitosina (5hmC) (Globisch et al., 2010; Ko et al., 2010). A 5hmC pode agir tanto como um produto intermediário na desmetilação ativa do DNA quanto na desmetilação passiva ao longo de sucessivas replicações, o que pode contribuir com a dinâmica da metilação do DNA (Tahiliani et al., 2009). Além disso, demonstrou-se que Tet1 e Tet2 são expressas em células tronco embrionárias (Ito et al., 2010) e que 5hmC desempenha importante papel na manutenção e diferenciação destas células (Koh et al., 2011). No entanto, o papel da 5hmC e das proteínas Tet tanto na fisiologia normal quanto em doenças como o câncer ainda não está claro. Utilizando um modelo linear de progressão do melanoma, observamos aumento na expressão gênica de Tet1 nas linhagens celulares correspondendo a melanócitos pré-malignos (4C) e células de melanoma não metastático (4C11-), comparado a melanócitos não tumorigênicos (melan-a) e células de melanoma metastático (4C11+). Em relação à expressão proteica, há um aumento da expressão de Tet1 nas linhagens 4C e 4C11+, o que pode ser relacionado às fases de transição epitélio-mesênquima (EMT) e mesênquima-epitélio (MET), respectivamente. Além disso, constatamos aumento na expressão gênica e proteica de Tet2 na linhagem metastática 4C11+, o que pode indicar diferenças funcionais entre as proteínas Tet1 e Tet2. Também verificamos aumento significativo do conteúdo de 5hmC na linhagem 4C11+, o que se correlaciona com maior expressão gênica e proteica de Tet2. Por fim, linhagens humanas de melanoma metastático menos agressivas apresentaram aumento significativo na expressão dos genes TET1 ...

Estudo da interação entre a via genética do microRNA156/squamosa promoter-binding protein-like e brassinosteróides durante o desenvolvimento de Arabidopsis thaliana

Pós-graduação em Ciências Biológicas (Genética) - IBB

Expression of Vascular Endothelial Growth Factor (VEGF) in Macrophages, Fibroblasts, and Endothelial Cells in Pterygium Treated with 5-Fluorouracil

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Influence of Insulin-like Growth Factor I (IGF-I) on the survival and the in vitro development of caprine preantral follicles

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Contrasting effects of nitric oxide and corticotropin-releasing factor within the dorsal periaqueductal gray on defensive behavior and nociception in mice

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)