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 re sponses through ICAM-1 expression, cytokine secretion (including TNF-alpha) , and regulation of blood-brain barrier permeability, Because ICAM-1 transd uces intracellular signals in lymphocytes and endothelial cells, we investi gated 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 trans cription factor cAMP response element-binding protein. We show that ICAM-1 binding induces cAMP accumulation and activation of the mitogen-activated p rotein kinase extracellular signal-regulated kinase, Both pathways are resp onsible for cAMP response element-binding protein phosphorylation and TNF-a lpha secretion. Moreover, these responses are partially dependent protein k inase C, which acts indirectly, as a common activator of cAMP/protein kinas e A and extracellular signal-regulated kinase pathways. These results const itute the first evidence of ICAM-1 coupling to intracellular signaling path ways in glial cells and demonstrate the convergence of these pathways onto transcription factor regulation and TNF-alpha secretion. They strongly sugg est that ICAM-1-dependent cellular adhesion to astrocytes could contribute to the inflammatory processes observed during leukocyte infiltration in the CNS.