Nuclear receptors take center stage in Th17 cell–mediated autoimmunity
Jennifer J. Heller, Ju Qiu, Liang Zhou
Jennifer J. Heller, Ju Qiu, Liang Zhou
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Commentary

Nuclear receptors take center stage in Th17 cell–mediated autoimmunity

Abstract

Liver X receptors (LXRs) are nuclear receptors involved in cholesterol homeostasis. Notably, they are also expressed by T cells and are involved in regulating T cell proliferation and differentiation. In this issue of the JCI, Cui et al. have elucidated the molecular mechanism underlying the effects of LXR activation on a subset of T cells known as Th17 cells in mice and humans. Specifically, they showed that LXR-induced Srebp-1 inhibits Il17 transcription by binding to the Il17 promoter through interaction with the aryl hydrocarbon receptor (Ahr), a transcription factor known to enhance Th17 cell responses.

Authors

Jennifer J. Heller, Ju Qiu, Liang Zhou

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Figure 1

Molecular mechanisms underlying LXR-mediated negative regulation of IL-17 expression in Th17 cells.

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Molecular mechanisms underlying LXR-mediated negative regulation of IL-1...
(A) In this issue of the JCI, Cui et al. report that Ahr, a ligand-dependent transcription factor, increases IL-17 expression by binding to the Il17 promoter (13). (B) LXR activation by its agonists induces and activates Srebp-1. A putative binding site of Srebp-1 is found at the E-box element on the Il17 promoter that overlaps with the Ahr-binding site, suggesting that Srebp-1 competes with Ahr for binding to this region of the Il17 promoter to suppress the activating effects of Ahr on IL-17 expression. Srebp-1 interacts with the PAS domain of Ahr, subsequently blocking the enhancement of Il17 transcription. LXR activation also inhibits the expression of other genes implicated in Th17 cell differentiation (e.g., Ahr).