Modes of action of aspirin-like drugs: salicylates inhibit erk activation and integrin-dependent neutrophil adhesion.
The anti-inflammatory effects of high-dose salicylates are well recognized, incompletely understood and unlikely due entirely to cyclooxygenase (COX) inhibition. We have previously reported a role for activation of the kinase Erk in CD11b/CD18 integrin-dependent adhesiveness of human neutrophils, a critical step in inflammation. We now report the effects of salicylates on neutrophil Erk and adhesion. Exposure of neutrophils to aspirin or sodium salicylate (poor COX inhibitor) inhibited Erk activity and adhesiveness of formylmethionyl-leucyl-phenylalanine- and arachidonic acid-stimulated neutrophils, consistent with anti-inflammation but not COX inhibition (IC50s = 1-8 mM). In contrast, indomethacin blocked neither Erk nor adhesion. Inhibition of Mek (proximal activator of Erk) also blocked stimulation of Erk and adhesion by formylmethionyl-leucyl-phenylalanineand arachidonic acid. Salicylate inhibition of Erk was independent of protein kinase A activation and generation of extracellular adenosine. These data are consistent with a role for Erk in stimulated neutrophil adhesion, and suggest that anti-inflammatory effects of salicylates may be mediated via inhibition of Erk signaling required for integrin-mediated responses.
Pillinger
M H
MH
Department of Medicine, Room NB16N1, New York University Medical Center, 550 First Avenue, New York, NY 10016, USA. michael.pillinger@mccm.med.nyu.edu
Capodici
C
C
Rosenthal
P
P
Kheterpal
N
N
Hanft
S
S
Philips
M R
MR
Weissmann
G
G
D000082:Acetaminophen / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology; D016718:Arachidonic Acid / Q000494:pharmacology; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018821:CD18 Antigens / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000097:blood*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002449:Cell Aggregation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D016177:Macrophage-1 Antigen / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D012980:Sodium Salicylate / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D015703:Antigens, CD; D018821:CD18 Antigens; D016861:Cyclooxygenase Inhibitors; D016177:Macrophage-1 Antigen; D016718:Arachidonic Acid; D000082:Acetaminophen; D009240:N-Formylmethionine Leucyl-Phenylalanine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate; D001241:Aspirin; D012980:Sodium Salicylate