SODIUM-SALICYLATE INDUCES APOPTOSIS VIA P38 MITOGEN-ACTIVATED PROTEIN-KINASE BUT INHIBITS TUMOR NECROSIS FACTOR-INDUCED C-JUN N-TERMINAL KINASE STRESS-ACTIVATED PROTEIN-KINASE ACTIVATION

In a previous study, we demonstrated that sodium salicylate (NaSal) se lectively inhibits tumor necrosis factor (TNF)-induced activation of t he p42 and p44 mitogen-activated protein kinases (MAPKs) (known as ext racellular signal-regulated kinases). Here we show that in normal huma n FS-4 fibroblasts NaSal inhibits TNF-induced activation of another me mber of the MAPK family, the c-Jun N-terminal kinase/stress-activated protein kinase, c-Jun N-terminal kinase activation induced by interleu kin 1 or epidermal growth factor was less strongly inhibited by NaSal. Unexpectedly, treatment of FS-4 cells with NaSal alone produced a str ong activation of p38 MAPK and cell death by apoptosis, NaSal-induced apoptosis was blocked by the selective p38 MAPK inhibitor SE-203580, i ndicating that p38 MARK serves as a mediator of NaSal-induced apoptosi s in human fibroblasts, Activation of p38 MAPK and the resulting induc tion of apoptosis may be important in the demonstrated antineoplastic actions of nonsteroidal anti-inflammatory drugs.