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) activated endothelial cells to increase their interaction with monocytes but not neutrophils, inducing monocyte but not neutrophil binding and synthesis of monocyte chemotactic protein-1 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 induction of monocyte binding and mRNA levels for M-CSF by MM-LDL were not inhibited in protein kinase C-depleted endothelial cells. A number of our studies indicate that cAMP is the second messenger for the effects of MM-LDL cited above. Incubation of endothelial cells with MM-LDL caused a 173% increase in intracellular cAMP levels. Agents which increased cAMP levels, including cholera toxin, pertussis toxin, dibutyryl cAMP, and isoproterenol mimicked the actions of MM-LDL. Agents which elevated cAMP were also shown to activate NF kappa B, suggesting a role for this transcription factor in activation of monocyte-endothelial interactions. Although endothelial leukocyte adhesion molecule (ELAM) mRNA synthesis can be regulated by NF kappa B, ELAM was not expressed and ELAM mRNA was only slightly elevated in response to MM-LDL. We present evidence that induction of neutrophil binding by LPS is actually suppressed by agents that elevated cAMP levels.
Department of Pathology, University of California School of Medicine, Los Angeles 90024-1732.
F
F
Parhami
Z T
ZT
Fang
A M
AM
Fogelman
A
A
Andalibi
M C
MC
Territo
J A
JA
Berliner
D000818:Animals; D023181:Antimicrobial Cationic Peptides; D001483:Base Sequence; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000473:pathology*; D007962:Leukocytes / Q000166:cytology*; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000502:physiology*; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D010084:Oxidation-Reduction; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D011817:Rabbits; D015290:Second Messenger Systems; D015398:Signal Transduction
D023181:Antimicrobial Cationic Peptides; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D011506:Proteins; D012333:RNA, Messenger; D016173:Macrophage Colony-Stimulating Factor; D000242:Cyclic AMP