Abstract
The current study was to investigate the interaction between Helicobacter pylori and human dendritic cells (DCs). Whether impaired DC function can influence the outcome of H. pylori infections. Human monocyte-derived DCs (MDDCs) from five gastric cancer patients and nine healthy controls were stimulated with H. pylori. Maturation markers of MDDC were examined by flow cytometry. IL-10 and TNF-α released by MDDCs and IL-17 produced by T cells were measured by ELISA. Regulatory signaling pathways of IL-10 were examined by ELISA, western blotting, and chromatin immunoprecipitation assay. The results showed that as compared with healthy individuals, the maturation marker CD40 in MDDCs, IL-17A expression from T cells, and IL-10 expression from MDDCs were significantly lower in gastric cancer patients. Blocking DC-SIGN, TLR2, and TLR4 could reverse H. pylori-associated IL-10 production. Activation of the p38 MAPK and NF-kB signaling pathways concomitant with decreased tri-methylated H3K9 and increased acetylated H3 accounted for the effect of H. pylori on IL-10 expression. Furthermore, upregulated IL-10 expression was significantly suppressed in H. pylori-pulsed MDDCs by histone acetyltransferase and methyltransferase inhibitors. Taken together, impaired DC function contributes to the less effective innate and adaptive immune responses against H. pylori seen in gastric cancer patients. H. pylori can regulate IL-10 production through Toll-like and DC-SIGN receptors, activates p-p38 MAPK signaling and the transcription factors NF-kB, and modulates histone modification.
Highlights
Helicobacter pylori is a Gram-negative, spiral-shaped bacterium that can colonize the human gastric mucosa
The host immune response to the bacterium is an intrinsic component in the pathogenesis of these diseases, and growing evidence indicates that dendritic cells (DCs) are involved in the response to H. pylori infection (Andres et al 2011; Bimczok et al 2010; Necchi et al 2009)
Weakened Th17 responses are induced by H. pylori-treated monocyte-derived DCs (MDDCs) from gastric cancer patients
Summary
Helicobacter pylori is a Gram-negative, spiral-shaped bacterium that can colonize the human gastric mucosa. These diverse outcomes have been attributed to the interplay of several factors, including H. pylori virulence, host genetic susceptibility and local immune responses, and environmental conditions. The VacA (vacuolating cytotoxin A) and the Cag (cytotoxin-associated gene) pathogenicity island of H. pylori have been shown to cause adverse outcomes, but these factors are not predictive of the development of gastric cancer in H. pylori-infected patients (Backert and Selbach 2008). The host immune response to the bacterium is an intrinsic component in the pathogenesis of these diseases, and growing evidence indicates that dendritic cells (DCs) are involved in the response to H. pylori infection (Andres et al 2011; Bimczok et al 2010; Necchi et al 2009). Mouse studies have shown that DCs are recruited to the gastric mucosa after H. pylori infection (Kao et al 2006, 2010). Using two photon and confocal microscopy, Rescigno et al localized DCs to close to the surface epithelium of the normal intestine and showed that their cellular processes extend into the epithelial layer (Rescigno et al 2001)
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