Inhibition of p38 mitogen activated protein kinase increases lipopolysaccharide induced inhibition of apoptosis in neutrophils by activating extracellular signal-regulated kinase

Background. Prolonged polymorphonuclear neutrophil (PAIN) survival has been implicated in tissue injury after sepsis. Previously we reported that lipo polysaccharide (LPS) inhibits PMN apoptosis ilia the activation of the extr acellular signal-regulated kinase (ERK). Conversely, the p38 mitogen activa ted protein kinase (MAPK) Pathway is involved in the spontaneous opoptosis of PMNs. The interaction between these 2 Pathways and their ability to regu late apoptosis during sepsis remain largely undefined. We hypothesize that there is interaction between the ERK and p38 pathways during sepsis. Methods. PMNs were isolated from healthy volunteers by Ficoll gradient cent rifugation and red blood cell sedimentation. Cells were then pretreated for 1 hour with the ERK inhibitor (PD98059, 10 mu mol/L), p38 inhibitor (SB203 580, 1 mu mol/L), or vehicle. After treatment with LPS, apoptosis and MAPK activity were correlated. Results. LPS stimulation significantly inhibits PMN apoptosis compared with unstimulated cells. Furthermore, inhibition of ERK significantly abrogates this effect, whereas inhibition of p38 augments LPS induced inhibition of apoptosis. Elk-l phosphorylation (ERK target) is significantly increased by LPS alone and by inhibition of the p38 pathway during LPS stimulation. Thi s correlates with ERK phosphorylation by Western blot. Conclusions. These data show that p38 inhibition enhances ERK activity duri ng endotoxemia. Furthermore, these data suggest that cooperation between ER K and p38 MAPK Pathways dictates the apoptotic potential of PMNs during inf lammatory states.