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Dysregulated neutrophil (polymorphonuclear PMN) apoptosis is thought to contribute to the onset of adult respiratory distress syndrome (ARDS) in critically ill patients. Tumor necrosis factor-α (TNFα), which is present in elevated levels in the bronchoalveolar lavage fluid in patients with ARDS, is thought to play a central role in regulating PMN function in the lungs. Studies have shown that short-term culture with TNFα increases apoptosis yet extended culture with TNFα suppresses apoptosis. However, it is unclear whether this latter effect of TNFα is directly or indirectly mediated through production of anti-apoptotic cytokines such as interleukin (IL)-8. To investigate the role of IL-8 in TNFα-induced apoptosis PMN were exposed to TNFα (100 ng/mL) in the presence or absence of antibodies to IL-8, and the extent of apoptosis was assessed. An enzyme-linked immunoassay was used to measure levels of the anti-apoptotic cytokine IL-8, induced by TNFα-stimulation. Because TNFα may mediate its effect through various cell-signaling pathways, we next assessed the effect of kinase inhibition on the ability of TNFα to effect apoptosis and IL-8 production. Treatment with TNFα had a biphasic effect: at 4-8 h, apoptosis was increased but was markedly suppressed at 24 h (P < 0.05). PMN cultured for 24 h with TNFα also showed markedly increased levels of IL-8. Neutralization of IL-8 inhibited the ability of TNFα to suppress apoptosis (P < 0.05). Incubation of TNFα + p38-mitogen-activated protein kinase (MAPK) inhibitor SB202190 increased apoptosis (P < 0.01) and decreased IL-8 production to PMN control. To a lesser extent, incubation of TNFα with inhibitors to NF-κB (SN50) and PI3K (LY294002) also increased apoptosis and decreased IL-8 production (P < 0.05). These data illustrate a novel mechanism by which TNFα can indirectly elicit an anti-apoptotic effect via p38-MAPK induced release of the anti-apoptotic chemokine IL-8. The exploitation of such a pathway represents a potential target for regulation of PMN-mediated acute lung injury.