ICAM-1-coupled signaling pathways in astrocytes converge to cyclic AMP response element-binding protein phosphorylation and TNF-alpha secretion.
In the CNS, astrocytes play a key role in immunological and inflammatory responses through ICAM-1 expression, cytokine secretion (including TNF-alpha), and regulation of blood-brain barrier permeability. Because ICAM-1 transduces intracellular signals in lymphocytes and endothelial cells, we investigated in the present study ICAM-1-coupled signaling pathways in astrocytes. Using rat astrocytes in culture, we report that ICAM-1 binding by specific Abs induces TNF-alpha secretion together with phosphorylation of the transcription factor cAMP response element-binding protein. We show that ICAM-1 binding induces cAMP accumulation and activation of the mitogen-activated protein kinase extracellular signal-regulated kinase. Both pathways are responsible for cAMP response element-binding protein phosphorylation and TNF-alpha secretion. Moreover, these responses are partially dependent protein kinase C, which acts indirectly, as a common activator of cAMP/protein kinase A and extracellular signal-regulated kinase pathways. These results constitute the first evidence of ICAM-1 coupling to intracellular signaling pathways in glial cells and demonstrate the convergence of these pathways onto transcription factor regulation and TNF-alpha secretion. They strongly suggest that ICAM-1-dependent cellular adhesion to astrocytes could contribute to the inflammatory processes observed during leukocyte infiltration in the CNS.
Etienne-Manneville
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S
Laboratoire d'Immuno-Pharmacologie Moléculaire, Institut Cochin de Génétique Moléculaire, Université Paris VII, France. etienne@icgm.inserm.fr
Chaverot
N
N
Strosberg
A D
AD
Couraud
P O
PO
D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004789:Enzyme Activation / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding / Q000276:immunology; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D012694:Serine; D000242:Cyclic AMP; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases