Interactions between alveolar macrophages (AMs) and epithelial cells may promote inflammatory responses to air pollution particles. Normal rat AMs, the alveolar type II epithelial cell line RLE-6TN (RLE), or cocultures of both cell types were incubated with various particles (0–50 μ g/ml) for 24 h, followed by assay of released TNF- α and MIP-2. The particles used included titanium dioxide (TiO₂), α -quartz (SiO₂), residual oil fly ash (ROFA), or urban air particles (UAP). For all particles, a dose-dependent increase in TNF- α and MIP-2 release was observed in AM + RLE co-cultures but not in RLE or AM monoculture. AM + RLE co-culture also synergistically enhanced basal levels of tumor necrosis factor (TNF)- α and macrophage inflammatory protein (MIP)-2. In contrast, when AMs were co-cultured with fibroblasts, basal and particle-induced TNF- α and MIP-2 were similar to levels found in AM monoculture. Particle uptake by AMs was similar in mono- or AM + RLE co-culture. Increased basal and particle-induced cytokine release were not observed when the AMs were physically separated from the RLE. This contact-dependent cytokine potentiation could not be blocked with anti-CD18/anti-CD54, arginine-glycine-aspartate (RGD) peptide, or heparin. We conclude that in vitro inflammatory responses to particles are amplified by contact-dependent interactions between AMs and epithelial cells. AM-epithelial co-culture may provide a useful model of in vivo particle effects.