To better understand the mechanisms by which neutrophils migrate to the airway lumen during an inflammatory response, we constructed an in vitro model system to examine the interactions of human neutrophils, human lung epithelial cells, mediators, and proinflammatory cytokines. We directly compared neutrophil movement through three lung epithelial cell lines, A549, H441, and 16-HBE-14o, in response to three chemoattractants, FMLP, LTB4, and IL-8, and the proinflammatory cytokines IL-1 alpha and beta and TNF alpha. While there was variation in the responses to the chemotaxins, there was no correlation between the transmonolayer electrical resistance and the ability of the neutrophils to migrate across the epithelia in response to the agents used. FMLP, IL-8, and LTB4 induced dose- and time-dependent neutrophil migration across all three epithelia. However, TNF alpha- and IL-1-induced neutrophil migration occurred only through monolayers that produced soluble chemoattractants in response to these cytokines. Although all three epithelia produced low amounts of IL-8 constitutively, the capacity of IL-1 and TNF alpha to induce transepithelial migration was directly associated with the ability of the epithelia to produce large amounts of IL-8 in response to IL-1 and TNF alpha. We conclude that the phenotype of the epithelial cell (e.g., capacity to produce IL-8) affects stimulated neutrophil transepithelial migration.