The orphan nuclear receptor ROR alpha is a negative regulator of the inflammatory response

Retinoid-related orphan receptor alpha (ROR alpha) (NR1F1) is a member of t he nuclear receptor superfamily whose biological functions are largely unkn own. Since staggerer mice, which carry a deletion in the ROR alpha gene, su ffer from immune abnormalities, we generated an adenovirus encoding ROR alp ha1 to investigate its potential role in control of the inflammatory respon se. We demonstrated that ROR alpha is expressed in human primary smooth-mus cle cells and that ectopic expression of ROR alpha1 inhibits TNF alpha -ind uced IL-6, IL-8 and COX-2 expression in these cells. ROR alpha1 negatively interferes with the NF-kappaB signalling pathway by reducing p65 translocat ion as demonstrated by western blotting, immunostaining and electrophoretic mobility shift assays. This action of ROR alpha1 on NF-kappaB is associate d with the induction of I kappaB alpha, the major inhibitory protein of the NF-kappaB signalling pathway, whose expression was found to be transcripti onally upregulated by ROR alpha1 via a ROR response element in the I kappaB alpha promoter. Taken together, these data identify ROR alpha1 as a potent ial target in the treatment of chronic inflammatory diseases, including ath erosclerosis and rheumatoid arthritis.