Glucocorticoid induced leucine zipper mimic inhibits experimental autoimmune encephalomyelitis (119.7)

Abstract

Abstract Multiple sclerosis (MS) is a relapsing remitting neurological disease mediated by inflammatory cell infiltration in the brain and spinal cord followed by demyelination. The profound anti-inflammatory activity and the ability promote peripheral deletion of activated lymphocytes make glucocorticoids (GCs) the preferred agents in the management of relapse. The therapeutic efficacy of GCs is largely attributed to the inhibition of nuclear factor-κB (NF-κB), the master regulator of inflammatory responses. Peptides from different subunits of NF-κB complex have been shown to suppress inflammation in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Here, we report a novel strategy to selectively target activated NF-κB and regulate inflammation. Glucocorticoid induced leucine zipper (GILZ) is a recently described molecule transcriptionally upregulated by GCs. GILZ binds to and inhibits the nuclear translocation of NF-κB thereby suppressing transactivation of inflammatory mediators. This suggests that the anti-inflammatory activity of GCs can be attributed to the inducible upregulation of GILZ. Rationally designed GILZ-mimic protects mice against relapsing remitting EAE. Mechanistically treatment with GILZ-mimic suppresses nuclear translocation of p65, inhibits Th1 specific transcription factor T-bet and upregulates Th2 transcription factor GATA-3. In conclusion, our results suggest that the GILZ: p65 interaction is a potential target for multiple sclerosis.