Article ; Online: Impairment of a NIK-SIX Feedback Axis Results in Dysregulation of Intestinal Immune Homeostasis and Promotes Early-onset Fatal Spontaneous Colitis.
Iranian journal of immunology : IJI
2023 Volume 19, Issue 3, Page(s) 263–277
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 ...
| 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. |
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| MeSH term(s) | Animals ; Colitis/pathology ; Cytokines/metabolism ; Feedback, Physiological ; Homeodomain Proteins/metabolism ; Homeostasis ; Humans ; Mice ; Mice, Inbred C57BL ; NF-kappa B/metabolism ; Protein Serine-Threonine Kinases/metabolism ; RNA, Small Interfering ; NF-kappaB-Inducing Kinase |
| Chemical Substances | Cytokines ; Homeodomain Proteins ; NF-kappa B ; RNA, Small Interfering ; SIX1 protein, human ; Protein Serine-Threonine Kinases (EC 2.7.11.1) |
| Language | English |
| Publishing date | 2023-04-11 |
| Publishing country | Iran |
| Document type | Journal Article |
| ZDB-ID | 2616647-1 |
| ISSN | 1735-367X ; 1735-367X |
| ISSN (online) | 1735-367X |
| ISSN | 1735-367X |
| DOI | 10.22034/iji.2022.90031.1985 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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