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 recogn ized, incompletely understood and unlikely due entirely to cyclooxygen ase (COX) inhibition. We have previously reported a role for activatio n of the kinase Erk in CD11b/CD18 integrin-dependent adhesiveness of h uman neutrophils, a critical step in inflammation. We now report the e ffects of salicylates on neutrophil Erk and adhesion. Exposure of neut rophils 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-in flammation but not COX inhibition (IC(50)s = 1-8 mM). In contrast, ind omethacin blocked neither Erk nor adhesion. Inhibition of Mek (proxima l activator of Erk) also blocked stimulation of Erk and adhesion by fo rmylmethionyl-leucyl-phenylalanine- and arachidonic acid. Salicylate i nhibition of Erk was independent of protein kinase A activation and ge neration 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.