MINIMALLY MODIFIED LOW-DENSITY-LIPOPROTEIN INDUCED INFLAMMATORY RESPONSES IN ENDOTHELIAL-CELLS ARE MEDIATED BY CYCLIC ADENOSINE-MONOPHOSPHATE

We have previously shown that minimally oxidized LDL (MM-LDL) activate d endothelial cells to increase their interaction with monocytes but n ot neutrophils, inducing monocyte but not neutrophil binding and synth esis of monocyte chemotactic protein-I and monocyte colony-stimulating factor (M-CSF). In the present studies we have examined the signaling pathways by which this monocyte-specific response is induced. Both in duction of monocyte binding and mRNA levels for M-CSF by MM-LDL were n ot inhibited in protein kinase C-depleted endothelial cells. A number of our studies indicate that cAMP is the second messenger for the effe cts of MM-LDL cited above. Incubation of endothelial cells with MM-LDL caused a 173% increase in intracellular CAMP levels. Agents which inc reased cAMP levels, including cholera toxin, pertussis toxin, dibutyry l cAMP, and isoproterenol mimicked the actions of MM-LDL. Agents which elevated cAMP were also shown to activate NFkappaB, suggesting a role for this transcription factor in activation of monocyte-endothelial i nteractions. Although endothelial leukocyte adhesion molecule (ELAM) m RNA synthesis can be regulated by NFkappaB, ELAM was not expressed and ELAM mRNA was only slightly elevated in response to MM-LDL. We presen t evidence that induction of neutrophil binding by LPS is actually sup pressed by agents that elevated cAMP levels.