Inhibition of chemotactic peptide-induced neutrophil adhesion to vascular endothelium by cAMP modulators.
An early event associated with neutrophil-dependent tissue damage involves the adhesion of neutrophils to the vascular endothelium and the subsequent release of oxygen-derived free radicals and granule constituents. Elevations in intracellular cAMP are known to inhibit free radical release but not lysosomal enzyme release. The role of cAMP in FMLP-induced neutrophil adhesion was examined in this study by using an in vitro model of neutrophil-endothelial cell adhesion. FMLP stimulated a time- and concentration-dependent increase in human neutrophil adhesion to HUVEC. FMLP-mediated adhesion was inhibited by a diverse group of cAMP modulators: forskolin, isoproterenol, phosphodiesterase IV inhibitors (rolipram and Ro 20-1724), but not phosphodiesterase III inhibitors (milrinone and bemoradan). Endogenous adenosine has previously been shown to mediate FMLP-induced increases in cAMP enhanced in the presence of Ro 20-1724. In this study, adenosine deaminase prevented the inhibitory effects observed with rolipram and Ro 20-1724, implicating endogenous adenosine as a co-modulator of inhibition. FMLP stimulated neutrophil shape change and the surface expression of the beta 2 integrins CD11b/CD18 and CD11a/CD18. Both these responses were inhibited by rolipram but not bemoradan. With the use of 4,4'-diisothiocyanostilbene-2,2'disulfonic acid, we showed that mobilization of the intracellular pool of CD11b/CD18 paralleled adhesion. We conclude that neutrophil-endothelial cell adhesion is attenuated by elevating neutrophil intracellular cAMP and that inhibition of neutrophil CD11b/CD18 surface expression by cAMP accounts for this observed inhibition of adhesion.
Derian
C K
CK
R. W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477.
Santulli
R J
RJ
Rao
P E
PE
Solomon
H F
HF
Barrett
J A
JA
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D048588:Benzoxazines; D018821:CD18 Antigens / Q000096:biosynthesis; D002448:Cell Adhesion / Q000187:drug effects*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003594:Cytoplasmic Granules / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology*; D006801:Humans; D007231:Infant, Newborn; D007545:Isoproterenol / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D020105:Milrinone; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D010078:Oxazines / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D016897:Respiratory Burst; D020889:Rolipram; D014471:Umbilical Veins
D048588:Benzoxazines; D018821:CD18 Antigens; D016177:Macrophage-1 Antigen; D010078:Oxazines; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011728:Pyridones; D011760:Pyrrolidinones; D005576:Colforsin; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C062457:bemoradan; D020105:Milrinone; D020889:Rolipram; D007545:Isoproterenol; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid