Bacterial phagocytosis activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase cascades in human neutrophils.

The hypothesis that bacterial phagocy- tosis by human polymorphonuclear neutrophils (PMNs) stimulates MAPK cascades that regulate respiratory burst activation was tested. Extracellu- lar response kinase (ERK) and p38 kinase, but not c-Jun NH2-terminal kinase, activities were in- creased within 5 min of phagocytosis of plasma- opsonized Staphylococcus aureus (S-SA), reached maximum at 20-30 min, and remained elevated through 60 min. The role of Fcg receptors was examined using gamma globulin-opsonized SA (IgG-SA), whereas CR3 receptors were activated by particulate b-glucan. IgG-SA stimulated a maximal ERK activity at 30 min, whereas p38 activity was maximal at 5 min. b-glucan stimulated maximal ERK activity at 5 min and maximal p38 activity at 2 min. Non-opsonized bacteria were ingested at 10% of the level of S-SA and stimulated a minimal increase in ERK and p38 activity at 60 min. S-SA stimulation of ERK was inhibited by wortmannin, LY294002, and genistein, but not calphostin C; whereas p38 stimulation was inhibited by calphos- tin C and genistein, but not wortmannin and LY294002. Simultaneous measurement of phagocy- tosis and H2O2 production by flow cytometry was used to assess the role of ERKs and p38 kinase in phagocytosis. The MEK inhibitor PD098059 had no significant effect on phagocytosis or H2O2 pro- duction. The p38 kinase inhibitor SB203580 signifi- cantly attenuated H2O2 production, whereas phago- cytosis was unaffected. In conclusion, bacterial phagocytosis stimulates ERK and p38 activation by distinct signal transduction pathways. Phagocytosis- stimulated p38 kinase activity is necessary for optimal H2O2 production. J. Leukoc. Biol. 64: 835-844; 1998.