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α-Melanocyte-Stimulating Hormone Inhibits NF-κB Activation and IκBα Degradation in Human Glioma Cells and in Experimental Brain Inflammation

Abstract The neuropeptide α-melanocyte-stimulating hormone (α-MSH) modulates production of proinflammatory cytokines in brain tissue and in peripheral inflammatory cells. Transcription of the genes for these proinflammatory cytokines is regulated by the nuclear factor κB (NF-κB). NF-κB is also activated by proinflammatory cytokines. Degradation of the cytoplasmic inhibitor IκBα protein results in activation of NF-κB. Because of increasing evidence that NF-κB is involved in brain injury and inflammation and neurodegenerative disease, we examined whether α-MSH inhibits activation of NF-κB and limits degradation of IκBα protein induced by lipopolysaccharide (LPS) in human glioma cells (A-172) and in mouse brain. Electrophoretic mobility shift assays of nuclear extracts from A-172 cells and whole mouse brains stimulated with LPS revealed that α-MSH does suppress NF-κB activation. Western blot analysis demonstrated that α-MSH preserved expression of IκBα protein in vitro (glioma cells) and in vivo (brain tissue). Chloramphenicol acetyltransferase assay indicated that α-MSH suppresses NF-κB-dependent reporter gene expression induced by LPS in A-172 cells. The findings are consistent with the possibility that the anti-inflammatory action of α-MSH in CNS inflammation occurs via modulation of NF-κB activation by peptide-induced inhibition of degradation of IκBα protein.