Dataset Information

Epigenetic control of the host gene by commensal bacteria in large intestinal epithelial cells.

ABSTRACT: Intestinal epithelial cells (IECs) are continuously exposed to large numbers of commensal bacteria but are relatively insensitive to them, thereby averting an excessive inflammatory reaction. We have previously reported that the hyporesponsiveness of a human IEC line to LPS was primarily the result of a down-regulation of TLR4 gene transcription through epigenetic mechanisms. In the present study we show that DNA methylation in the 5' region of the TLR4 gene is significantly higher in IECs than in splenic cells in vivo. The methylation was shown to be dependent on the differentiation state of the IECs, as the differentiated IEC population that expressed higher levels of intestinal alkaline phosphatase (IAP) also displayed greater methylation and lower expression of the TLR4 gene than the undifferentiated population. The IAP(high), differentiated population also showed less abundant expression of CDX2, the transcription factor required for the development of the intestine, than the IAP(low), undifferentiated population. Overexpression of CDX2 in an IEC line decreased the methylation level of the TLR4 gene, increased transcriptional promoter activity of the gene, and increased responsiveness to the TLR4 ligand. Furthermore, the methylation level of the TLR4 gene was significantly lower in IECs of the large intestine of germ-free mice than in those of conventional mice, whereas the level in IECs of the small intestine was almost equal between these mice, indicating that commensal bacteria contribute to the maintenance of intestinal symbiosis by controlling epigenetic modification of the host gene in the large intestine.

SUBMITTER: Takahashi K

PROVIDER: S-EPMC3195625 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Epigenetic control of the host gene by commensal bacteria in large intestinal epithelial cells.

Takahashi Kyoko K Sugi Yutaka Y Nakano Kou K Tsuda Masato M Kurihara Kenta K Hosono Akira A Kaminogawa Shuichi S

The Journal of biological chemistry 20110823 41

Intestinal epithelial cells (IECs) are continuously exposed to large numbers of commensal bacteria but are relatively insensitive to them, thereby averting an excessive inflammatory reaction. We have previously reported that the hyporesponsiveness of a human IEC line to LPS was primarily the result of a down-regulation of TLR4 gene transcription through epigenetic mechanisms. In the present study we show that DNA methylation in the 5' region of the TLR4 gene is significantly higher in IECs than ...[more]

PMID: 21862578

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Project description:Innate lymphoid cells (ILCs) are a recently characterized family of immune cells that have critical roles in cytokine-mediated regulation of intestinal epithelial cell barrier integrity. Alterations in ILC responses are associated with multiple chronic human diseases, including inflammatory bowel disease, implicating a role for ILCs in disease pathogenesis. Owing to an inability to target ILCs selectively, experimental studies assessing ILC function have predominantly used mice lacking adaptive immune cells. However, in lymphocyte-sufficient hosts ILCs are vastly outnumbered by CD4(+) T cells, which express similar profiles of effector cytokines. Therefore, the function of ILCs in the presence of adaptive immunity and their potential to influence adaptive immune cell responses remain unknown. To test this, we used genetic or antibody-mediated depletion strategies to target murine ILCs in the presence of an adaptive immune system. We show that loss of retinoic-acid-receptor-related orphan receptor-?t-positive (ROR?t(+)) ILCs was associated with dysregulated adaptive immune cell responses against commensal bacteria and low-grade systemic inflammation. Remarkably, ILC-mediated regulation of adaptive immune cells occurred independently of interleukin (IL)-17A, IL-22 or IL-23. Genome-wide transcriptional profiling and functional analyses revealed that ROR?t(+) ILCs express major histocompatibility complex class II (MHCII) and can process and present antigen. However, rather than inducing T-cell proliferation, ILCs acted to limit commensal bacteria-specific CD4(+) T-cell responses. Consistent with this, selective deletion of MHCII in murine ROR?t(+) ILCs resulted in dysregulated commensal bacteria-dependent CD4(+) T-cell responses that promoted spontaneous intestinal inflammation. These data identify that ILCs maintain intestinal homeostasis through MHCII-dependent interactions with CD4(+) T cells that limit pathological adaptive immune cell responses to commensal bacteria.

Dataset Information

Epigenetic control of the host gene by commensal bacteria in large intestinal epithelial cells.

Publications

Epigenetic control of the host gene by commensal bacteria in large intestinal epithelial cells.

Similar Datasets

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