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Secretion1
*
Laboratoire d’Immuno-Pharmacologie Moléculaire, Institut Cochin de Génétique Moléculaire, Université Paris VII, Paris, France; and
Neurotech SA, Parc Club Orsay, Orsay, France
In the CNS, astrocytes play a key role in immunological and
inflammatory responses through ICAM-1 expression, cytokine secretion
(including TNF-
), 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- 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- 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- 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.
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