P38 MITOGEN-ACTIVATED PROTEIN KINASE-DEPENDENT AND KINASE-INDEPENDENTINTRACELLULAR SIGNAL-TRANSDUCTION PATHWAYS LEADING TO APOPTOSIS IN HUMAN NEUTROPHILS

Human neutrophils undergo apoptosis spontaneously when cultured in vit ro; however, the signal transduction pathways involved remain largely unknown, In some cell types, c-Jun NH2-terminal kinase and p38 mitogen -activated protein kinase (MAPK) have been implicated in the pathways leading to stress-induced apoptosis, In this study, we bean to define two pathways leading to apoptosis in the neutrophil induced either by stress stimuli (UV, hyperosmolarity, sphingosine) or by anti-Fas antib ody or overnight culture in vitro (spontaneous apoptosis), Apoptosis i nduced by stress stimuli activated p38 MAPK, and apoptosis was inhibit ed by the specific p38 MAPK inhibitor, 3-dihydro-5-(4-puridinyl)imidaz o(2,1-beta)thiazole dihydrochloride, Furthermore, differentiation of H L-60 cells toward the neutrophil phenotype resulted in a loss in c-Jun NH2-terminal kinase activation with concomitant acquisition of formyl methionylleucylphenylalanine-stimulatable and stress-inducible p38 MAP K activity as well as apoptosis blockade by the p38 MAPK inhibitor, In contrast, anti-Fas-induced or spontaneous apoptosis occurred independ ent of p38 MAPK activation and was not blocked by the inhibitor, Both pathways appear to utilize member(s) of the caspase family, since pret reatment with either Val-Ala-Asp-fluoromethyl ketone or Asp-Glu-Val As p-fluoromethyl ketone inhibited apoptosis induced by each of the stimu li, We propose the presence of at least two pathways leading to apopto sis in human neutrophils, a stress-activated pathway that is dependent on p38 MAPK activation and an anti-FAS/spontaneous pathway that is p3 8 MAPK-independent.