alpha-melanocyte-stimulating hormone inhibits NF-kappa B activation and I kappa B alpha degradation in human glioma cells and in experimental brain inflammation

The neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) modulates production of proinflammatory cytokines in brain tissue and in peripheral inflammatory cells. Transcription of the genes for these proinflammatory cy tokines is regulated by the nuclear factor kappa B (NF-kappa B). NF-kappa B is also activated by proinflammatory cytokines. Degradation of the cytopla smic inhibitor I kappa B alpha protein results in activation of NF-kappa B. Because of increasing evidence that NF-kappa B is involved in brain injury and inflammation and neurodegenerative disease, we examined whether alpha- MSH inhibits activation of NF-kappa B and limits degradation of I kappa B a lpha protein induced by lipopolysaccharide (LPS) in human glioma cells (A-1 72) and in mouse brain. Electrophoretic mobility shift assays of nuclear ex tracts from A-172 cells and whole mouse brains stimulated with LPS revealed that alpha-MSH does suppress NF-kappa B activation. Western blot analysis demonstrated that alpha-MSH preserved expression of I kappa B alpha protein in vitro (glioma cells) and in vivo (brain tissue). Chloramphenicol acetyl transferase assay indicated that alpha-MSH suppresses NF-kappa B-dependent reporter gene expression induced by LPS in A-172 cells. The findings are co nsistent with the possibility that the anti-inflammatory action of alpha-MS H in CNS inflammation occurs via modulation of NF-kappa B activation by pep tide-induced inhibition of degradation of I kappa B alpha protein. (C) 1999 Academic Press.