NF-?B activation by N-CAM and cytokines in astrocytes is regulated by multiple protein kinases and redox modulation

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Abstract
Interaction of the neural cell adhesion molecule (N‐CAM) with astrocytes activates a transcription factor, NF‐κB, that mediates inflammatory responses after neural injury. Here we describe intracellular signaling events that link N‐CAM binding to NF‐κB–mediated transcription. Addition of the third immunoglobulin domain of N‐CAM (Ig III), which mimics the activity of intact N‐CAM, or of cytokines (interleukin‐1β or tumor necrosis factor‐α), increased transcription from an NF‐κB–responsive luciferase reporter gene construct that had been transiently transfected into neonatal rat forebrain astrocytes. NF‐κB activity induced by Ig III or cytokines was decreased by inhibition of nonreceptor protein tyrosine kinases (PTKs), phospholipase C, protein kinase C (PKC), calcium/calmodulin‐dependent protein kinase II (CaMKII), or oxidative stress. Inhibition of PKC blocked nuclear translocation of NF‐κB protein while binding of NF‐κB to DNA was decreased by modulation of redox homeostasis. In contrast, inhibition of CaMKII and nonreceptor PTKs altered neither nuclear translocation nor DNA binding, suggesting that these kinases affect NF‐κB transactivation. A number of agents that inhibit NF‐κB activation in other cell types did not affect activation in astrocytes. These findings suggest that activation of NF‐κB by N‐CAM and cytokines in astrocytes involves multiple signals that differentially affect NF‐κB nuclear translocation, DNA binding, and transactivation. GLIA 33:45–56, 2001.