Loss of IκB-β is associated with prolonged NF-κB activity in human glial cells

Nuclear factor-kappaB (NF-kappaB) is an inducible transcription factor central in the regulation of expression of a wide variety of genes and synthesis of several proteins involved in the generation of the immune response and inflammatory processes. In resting cells, NF-kappaB is maintained in an inactive state through cytoplasmic retention by I kappaB inhibitors. Stimulation of cells with a wide variety of inducers results in proteolytic degradation of these I kappaB proteins, leading to activation of NF-kappaB. The present study shows that interleukin-1 (IL-1) causes persistent activation of NF-kappaB in glial cells. Stimulation with IL-1 also causes rapid but transient degradation of I kappaB-alpha and I kappaB-epsilon. However, NF-kappaB remains active even after these I kappaB isoforms have returned to control levels. In contrast, the I kappaB-beta isoform fails to reappear following its initial degradation by IL-1, coincident with sustained activation of NF-kappaB. In addition, in vivo overexpression of the various I kappaB isoforms revealed that I kappaB-beta is the only isoform that has the ability to inhibit IL-1-induced NF-kappaB-driven transcription. The findings also suggest 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 indicate that I kappaB-beta is the key regulator of the activity of NF-kappaB in human glial cells.