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. 2012 Oct;96(1):211-20.
doi: 10.1007/s00253-012-4034-z. Epub 2012 Apr 13.

Impaired dendritic cell maturation and IL-10 production following H. pylori stimulation in gastric cancer patients

Lin-Li Chang  1 , Sheng-Wen Wang, I-Chen Wu, Fang-Jung Yu, Yu-Chung Su, Ye-Pin Chen, Deng-Chyang Wu, Chang-Hung Kuo, Chih-Hsing Hung
Affiliations

Impaired dendritic cell maturation and IL-10 production following H. pylori stimulation in gastric cancer patients

Lin-Li Chang et al. Appl Microbiol Biotechnol. 2012 Oct.

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.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Expression of surface markers on H. pylori-primed MDDCs from gastric cancer patients and healthy individuals. Mean fluorescence intensity (MFI) expression of co-stimulatory molecules a CD40, b HLA-DR, c CD80, and d CD86 in MDDCs was detected by flow cytometry. CD40 expression was significantly lower in MDDCs from gastric cancer patients. One of three representative experiments is shown. Isotype control: black, normal control: light gray, patient control: heavy gray, normal H. pylori 1:200: black plot line, patient H. pylori 1:200: black heavy line. *p = 0.05; NS non significant
Fig. 2
Fig. 2
IL-17A expression induced by H. pylori-treated MDDCs differs between gastric cancer patients and healthy individuals. Induction of IL-17A production after co-culture of naïve T cell with H. pylori pulsed MDDCs from healthy individuals or gastric cancer patients. IL-17A expression differs between these two groups, as measured by ELISA. Data are presented as means and standard deviation of three independent experiments. Mann–Whitney tests were used to calculate statistical significance. *p <0.05; **p <0.01
Fig. 3
Fig. 3
Production of IL-10 and TNF-α from MDDCs after H. pylori stimulation. H. pylori induces IL-10 (a) and TNF-α (b) production by MDDCs from healthy individuals in a dose- and time-dependent manner (n = 9 individuals). c MDDCs from five gastric cancer patients did not produce significant levels of IL-10 after H. pylori stimulation, and IL-10 production was significantly lower than in MDDCs from healthy individuals. d TNF-α expression did not differ between gastric cancer patients and healthy individuals after H. pylori exposure. **p <0.01, *p <0.05 was considered significant versus untreated cells, NS non-significant difference. cMDDC MDDC from healthy individuals
Fig. 4
Fig. 4
H. pylori induced IL-10 production via DC-SIGN, TLR2, and TLR4 receptors in MDDCs. IL-10 expression in H. pylori-infected MDDCs from nine healthy individuals in the absence or presence of anti-DC-SIGN, TLR2, or TLR4 antibody, either alone or in the indicated combination for 1 h prior to the treatment of MDDCs with H. pylori, was evaluated by ELISA. Statistical significance was determined with one-way ANOVA test. **p <0.01 was considered significant compared with cells not treated with antibody. TLR2 toll-like receptor 2, TLR4 toll-like receptor 4
Fig. 5
Fig. 5
H. pylori increases IL-10 production in MDDCs via the p38 MAPK and p65 NF-kB pathways. a The level of IL-10 expression in H. pylori-infected MDDCs in the presence of 2 μM I-kB inhibitor BAY-117082, p38 phosphorylation inhibitor SB203580, JNK phosphorylation inhibitor SP600125, and ERK phosphorylation inhibitor PD98059. b Western blot analyses of phosphorylated p65, p38, ERK, JNK (pp65, pp38, pERK, pJNK), and total p65, p38, ERK, JNK, β-actin was used for internal controls. ***p <0.001
Fig. 6
Fig. 6
H. pylori regulates IL-10 production via histone modifications in healthy controls. A ChIP assay was used to analyze the relative levels of a acetylated H3 and b acetylated H4, c tri-methylated H3K4, d H3K9, e H3K36, and f H3K79 at the IL-10 gene promoter region of nine healthy individuals. g IL-10 production was significantly lower in MDDCs treated with the histone acetyltransferase inhibitor anacardic acid (AA) and the histone methyltransferase inhibitor MTA. *p <0.05, **p <0.01, ***p <0.001
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