TUMOR NECROSIS FACTOR-ALPHA-INDUCED PHOSPHORYLATION AND ACTIVATION OFCYTOSOLIC PHOSPHOLIPASE A(2) ARE ABROGATED BY AN INHIBITOR OF THE P38MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE IN HUMAN NEUTROPHILS

The role of the newly identified p38 mitogen-activated protein kinase (MAP kinase) in terminally differentiated cells, such as human neutrop hils, is totally unknown. In order to examine the possible role of thi s MAP kinase in the phosphorylation and activation of cytoplasmic phos pholipase A(2) (cPLA(2)), we tested the effect of the recently synthes ized inhibitor of p38 MAP kinase, SE 203580, on the phosphorylation an d activation of both p38 MAP kinase and cPLA(2). We found that while t umour necrosis factor-alpha (TNF-alpha)-stimulated tyrosine phosphoryl ation of p38 MAP kinase is affected only slightly by SE 203580, its st imulated kinase activity is greatly reduced in human neutrophils in su spension treated with this inhibitor. Furthermore, the TNF-alpha-stimu lated phosphorylation and activation of cPLA(2) are completely abolish ed in cells treated with SE 203580. Based on these data, it is reasona ble to conclude that an SE 203580-sensitive kinase, or kinases and/or phosphatases, are involved in the phosphorylation and activation of cP LA(2) in intact human neutrophils in suspension stimulated by TNF-alph a. The possible role of the p38 MAP kinase cascade in the phosphorylat ion and activation of cPLA(2) is discussed.