Loss of I kappa B-beta is associated with prolonged NF-kappa B activity inhuman glial cells

Nuclear factor-kappaB (NF-kappaB) is an inducible transcription factor cent ral in the regulation of expression of a wide variety of genes and synthesi s of several proteins involved in the generation of the immune response and inflammatory processes. In resting cells, NF-kappaB is maintained in an in active state through cytoplasmic retention by I kappaB inhibitors. Stimulat ion of cells with a wide variety of inducers results in proteolytic degrada tion of these I kappaB proteins, leading to activation of NF-kappaB. The pr esent study shows that interleukin-1 (IL-1) causes persistent activation of NF-kappaB in glial cells. Stimulation with IL-1 also causes rapid but tran sient degradation of I kappaB-alpha and I kappaB-epsilon. However, NF-kappa B remains active even after these I kappaB isoforms have returned to contro l levels. In contrast, the I kappaB-beta isoform fails to reappear followin g its initial degradation by IL-1, coincident with sustained activation of NF-kappaB. In addition, in vivo overexpression of the various I kappaB isof orms revealed that I kappaB-beta is the only isoform that has the ability t o inhibit IL-1-induced NF-kappaB-driven transcription. The findings also su ggest that the inability of I kappaB-alpha and I kappaB-epsilon to modulate NF-kappaB activity is due to their modification in viuo. These findings in dicate that I kappaB-beta is the key regulator of the activity of NF-kappaB in human glial cells.