NF-kappaB activation by N-CAM and cytokines in astrocytes is regulated by multiple protein kinases and redox modulation.
Interaction of the neural cell adhesion molecule (N-CAM) with astrocytes activates a transcription factor, NF-kappaB, that mediates inflammatory responses after neural injury. Here we describe intracellular signaling events that link N-CAM binding to NF-kappaB-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-1beta or tumor necrosis factor-alpha), increased transcription from an NF-kappaB-responsive luciferase reporter gene construct that had been transiently transfected into neonatal rat forebrain astrocytes. NF-kappaB 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-kappaB protein while binding of NF-kappaB 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-kappaB transactivation. A number of agents that inhibit NF-kappaB activation in other cell types did not affect activation in astrocytes. These findings suggest that activation of NF-kappaB by N-CAM and cytokines in astrocytes involves multiple signals that differentially affect NF-kappaB nuclear translocation, DNA binding, and transactivation.
Choi
J
J
Department of Neurobiology, The Scripps Research Institute, La Jolla, California 92037, USA.
Krushel
L A
LA
Crossin
K L
KL
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001930:Brain Injuries / Q000378:metabolism / Q000503:physiopathology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D016207:Cytokines; D019006:Neural Cell Adhesion Molecules; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases