Cyclic adenosine monophosphate regulates the expression of the intercellular adhesion molecule and the inducible nitric oxide synthase in brain endothelial cells

The authors studied whether cyclic AMP (cAMP), a widespread regulator of in flammation. modulates the cytokine-mediated expression of the intercellular adhesion molecule, intercellular adhesion molecule-1 (ICAM-1), and the inf lammatory nitric oxide synthase 2 (NOS-2), in primary and immortalized brai n endothelial cell cultures (GP8.3 cell line). When measured by enzyme-link ed immunosorbent assay (ELISA), ICAM-1 was constitutively expressed and was upregulated twofold by interleukin-1 beta, with no effect of interferon-ga mma. The NOS-2 activity, assessed by nitrite accumulation, was absent from untreated cultures but was induced by interleukin-1 beta and interferon-gam ma acting synergistically. Stimulation of cAMP-dependent pathways with fors kolin or dibutyryl cAMP decreased ICAM-1 protein expression, whereas it inc reased NOS-2 protein expression. For both ICA-1 and NOS-2, mRNA expression correlated with protein expression. Blockade of NOS activity with L-N-monom ethylargiuine (L-NMMA) did not alter ICAM-1 expression, indicating that the nitric oxide released by NOS-2 did not cause the down-regulation of ICAM-1 . Analysis of NF kappa B activation indicated that cAMP acted through a mec hanism other than inhibition of nuclear translocation of NF kappa B. The au thors conclude that cAMP modulates the expression of proinflammatory molecu les in brain endothelium. This suggests that inflammatory processes at the blood-brain barrier in vivo may be regulated by perivascular neurotransmitt ers via cAMP.