Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation
Guoliang Cui, Xia Qin, Lili Wu, Yuebo Zhang, Xiaoyan Sheng, Qiwen Yu, Hongguang Sheng, Beili Xi, Jingwu Z. Zhang, Ying Qin Zang
Guoliang Cui, Xia Qin, Lili Wu, Yuebo Zhang, Xiaoyan Sheng, Qiwen Yu, Hongguang Sheng, Beili Xi, Jingwu Z. Zhang, Ying Qin Zang
View: Text | PDF
Research Article

Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation

Abstract

Th17 cells are a subset of CD4+ T cells with an important role in clearing certain bacterial and fungal pathogens. However, they have also been implicated in autoimmune diseases such as multiple sclerosis. Exposure of naive CD4+ T cells to IL-6 and TGF-β leads to Th17 cell differentiation through a process in which many proteins have been implicated. We report here that ectopic expression of liver X receptor (LXR) inhibits Th17 polarization of mouse CD4+ T cells, while LXR deficiency promotes Th17 differentiation in vitro. LXR activation in mice ameliorated disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, whereas LXR deficiency exacerbated disease. Further analysis revealed that Srebp-1, which is encoded by an LXR target gene, mediated the suppression of Th17 differentiation by binding to the E-box element on the Il17 promoter, physically interacting with aryl hydrocarbon receptor (Ahr) and inhibiting Ahr-controlled Il17 transcription. The putative active site (PAS) domain of Ahr and the N-terminal acidic region of Srebp-1 were essential for this interaction. Additional analyses suggested that similar LXR-dependent mechanisms were operational during human Th17 differentiation in vitro. This study reports what we believe to be a novel signaling pathway underlying LXR-mediated regulation of Th17 cell differentiation and autoimmunity.

Authors

Guoliang Cui, Xia Qin, Lili Wu, Yuebo Zhang, Xiaoyan Sheng, Qiwen Yu, Hongguang Sheng, Beili Xi, Jingwu Z. Zhang, Ying Qin Zang

×

Figure 6

LXR activation suppresses IL-17 transcriptional activity through the promotion of Srebp-1 binding to the E-box element on the Il17 promoter.

Options: View larger image (or click on image) Download as PowerPoint
LXR activation suppresses IL-17 transcriptional activity through the pro...
(A) Jurkat cells were transfected with fragments of the mouse Il17 promoter linked to a firefly luciferase construct and cultured with or without T0901317 (2 μM) before luciferase reporter assays. (B) Mouse naive CD4+ T cells were cultured under Th1-, Th2-, Treg-, or Th17-inducing conditions for 4 days in the presence of the indicated drugs before real-time PCR analysis of Srebp1a and Srebp1c. Mouse macrophage cell line RAW264.7 (MF) and hepatocyte cell line Hepa 1-6 were included as controls. (C and D) Srebp-1 binding to the E-box element on the Il17 promoter in in vitro differentiated Th17 cells was assessed by EMSA (C) and ChIP (D). The primers used to detect ChIP signals are schematically represented in Supplemental Figure 1. Statistical analysis was performed between the LXR agonist–treated and untreated groups. (E) Srebp-1a and Srebp-1c expression plasmids were transfected into Jurkat cells for luciferase reporter assay. (F) Naive CD4+ T cells were cultured under Th17-inducing conditions with or without retroviral overexpression or knockdown of Srebp-1a/c before IL-17 staining. This experiment was repeated at least 3 times with similar results. Values indicate the percentage of IL-17+ cells.*P < 0.05, #P < 0.01, §P > 0.05. Data are expressed as mean ± SD in A, B, D, and E.