Yu Xia Zhao, Hong Mei, Yang Xin Huang, Jia Qing Chen
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引用次数: 0
Abstract
Background: The negative feedback circuit NIK-SIN could inhibit the systemic inflammation and protect mouse from endotoxic shock. However, the physiological significance of NIK-SIX feedback circuit in the maintenance of intestinal immune homeostasis and prevention of early-onset spontaneous colitis is not known.
Objective: To explore the role of NIK-SIX axis in the maintenance of intestinal immune homeostasis.
Methods: The conditional knockout of NIK encoding gene, Map3k14, in the Cd11c+ dendritic cells were generated by crossing Map3k14-flox mice with Cd11c-Cre mice. DSS was used for colitis models. The expression of cytokines in the intestinal immune cells, isolated from Map3k14-cKO mice were detected by qPCR. The siRNA molecules were used for the silencing of SIN-proteins. Then luciferase assays and chromatin immunoprecipitation combined with qPCR were applied for mechanism investigations.
Results: The expression of SIX1 and SIX2 protein in BMDMs from WT were significantly lower than in the Map3k14-cKO mice. In vitro, the NIK-/- human-derived circulating monocytes also failed to express SIX-proteins under the stimulation of non-canonical NF-κB agonists. The expression of cytokines was significantly decreased in human circulating monocytes with overexpression SIN-proteins. The expression of cytokines in macrophages, DCs and T cells isolated from Map3k14-cKO mice were significantly increased in the DSS-induced models. Higher expression of cytokines was observed in the SIN1-/- and SIN2-/- cells including human circulating monocytes, mouse-derived BMDMs, intestinal macrophages and DCs. SIN-proteins directly bound the promoter region of inflammatory genes.
Conclusion: NIK-SIX axis down-regulated inflammatory gene expression and plays a pivotal role in the maintenance of intestinal immune homeostasis.
期刊介绍:
The Iranian Journal of Immunology (I.J.I) is an internationally disseminated peer-reviewed publication and publishes a broad range of experimental and theoretical studies concerned with all aspects of immunology.