Inhibition of neutrophil adhesion by adenosine and an adenosine kinase inhibitor. The role of selectins.
Adenosine and adenosine analogues exhibit anti-inflammatory effects in vitro and in vivo, but their usefulness is limited by profound cardiovascular side effects. Therefore, we synthesized inhibitors of an enzyme involved in adenosine metabolism, adenosine kinase (AK) (EC 2.7.1.20), to enhance endogenous adenosine concentrations at sites of inflammation. GP-1-515 (4-amino-1-(5-amino-5-deoxy-1-beta-D- ribofuranosyl)-3-bromo-pyrazolo[3,4-d]pyrimidine), a novel AK inhibitor, decreased adhesion of activated human neutrophils to cultured endothelial cell monolayers by increasing local adenosine levels. The mechanism of inhibition in this assay seemed to involve selectin blockade and was independent of the beta 2 integrins. GP-1-515 and 2-chloroadenosine (a nonmetabolizable adenosine analogue) had no effect on the surface expression or shedding of adhesion molecules. An agent that disrupts the cytoskeleton, cytochalasin B, mimicked the effect of adenosine on cell adhesion. Interactions between L-selectin and the neutrophil cytoskeleton might be altered by adenosine and could contribute to adenosine-mediated adhesion inhibition.
Firestein
G S
GS
Gensia, Incorporated, San Diego, CA.
Bullough
D A
DA
Erion
M D
MD
Jimenez
R
R
Ramirez-Weinhouse
M
M
Barankiewicz
J
J
Smith
C W
CW
Gruber
H E
HE
Mullane
K M
KM
D015762:2-Chloroadenosine / Q000494:pharmacology; D000241:Adenosine / Q000378:metabolism / Q000494:pharmacology*; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D018821:CD18 Antigens / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000502:physiology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000502:physiology / Q000648:ultrastructure; D003864:Depression, Chemical; D019040:E-Selectin; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D019041:L-Selectin; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D012263:Ribonucleosides / Q000494:pharmacology*
D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D007375:Interleukin-1; D012263:Ribonucleosides; D019041:L-Selectin; C087698:GP 1-515; D015762:2-Chloroadenosine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000248:Adenosine Kinase; D000241:Adenosine