The nuclear receptor RORα exerts a bi-directional regulation of IL-6 in resting and reactive astrocytes

摘要

Astrocytes and one of their products, IL-6, not only support neurons but also mediate inflammation in the brain. Retinoid-related orphan receptor-α (RORα) transcription factor has related roles, being neuro-protective and, in peripheral tissues, anti-inflammatory. We examined the relation of RORα to astrocytes and IL-6 using normal and RORα loss-of-function mutant mice. We have shown RORα expression in astrocytes and its up-regulation by pro-inflammatory cytokines. We have also demonstrated that RORα directly trans-activates the Il-6 gene. We suggest that this direct control is necessary to maintain IL-6 basal level in the brain and may be a link between the neuro-supportive roles of RORα, IL-6, and astrocytes. Furthermore, after inflammatory stimulation, the absence of RORα results in excessive IL-6 up-regulation, indicating that RORα exerts an indirect repression probably via the inhibition of the NF-κB signaling. Thus, our findings indicate that RORα is a pluripotent molecular player in constitutive and adaptive astrocyte physiology.