NF-κB activation and IκBα dynamism involved in iNOS and chemokine induction in astroglial cells

This review will discuss the recent literature on the molecular mechanism of NF-kappaB activation, with special focus on I kappaB alpha dynamism involved in iNOS- and chemokine-induction in glial cells. NF-kappaB, a heterotrimer composed of p50, p65 (Rel A) and I kappaB alpha, has been shown to be activated by elimination of the regulatory subunit I kappaB alpha from the heterotrimer. The elimination of I kappaB alpha (formation of active NF-kappaB, p50 p65) is due to phosphorylation of serines 32 and 36 of I kappaB alpha, followed by polyubiquitination and 26S proteasomal degradation of I kappaB alpha. Experiments using stable clones of rat C6 glioma cells transfected with dominant negative I kappaB alpha (serines 32 and 36 replaced by alanine) suggest that NF-kappaB activation (phosphorylation of I kappaB alpha) is involved in LPS/IFN gamma- or IL-1 beta /IFN gamma -induced iNOS expression. Furthermore, the time courses of phosphorylation, ubiquitination of I kappaB alpha and proteasome activity after IL-1 beta treatment also suggest that 26S proteasomal degradation of I kappaB alpha is more crucial for chemokine expression in glial cells. (C) 2001 Elsevier Science Inc. All rights reserved.