MMP-12 is described to be involved in pulmonary inflammatory response. To determine the mechanisms linking macrophage metalloelastase (MMP-12) and inflammation, we examined the effect of recombinant human MMP-12 (rhMMP-12) catalytic domain on IL-8/CXCL8 production in cultured human airway epithelial (A549) cells. Stimulation with rhMMP-12 resulted in a concentration-dependent IL-8/CXCL8 synthesis 6 h later. Similar results were also observed in cultured Beas-2b bronchial epithelial cells. In A549 cells, synthetic MMPs inhibitors prevented rhMMP-12-induced IL-8/CXCL8 release. We further demonstrated that in A549 cells, rhMMP-12 induced transient, peaking at 5 min, activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). Selective MEK inhibitors (U0126 and PD98059) blocked both IL-8/CXCL8 release and ERK1/2 phosphorylation. IL-8/CXCL8 induction and ERK1/2 activation were preceded by epidermal growth factor receptor (EGFR) tyrosine phosphorylation, within 2 min, and were reduced by selective EGFR tyrosine kinase inhibitors (AG1478 and PD168393), by a neutralizing EGFR antibody and by small interfering RNA oligonucleotides directed against EGFR, implicating EGFR activation. In addition we observed an activation of c-Fos in A549 cells stimulated by rhMMP-12, dependent on ERK1/2. Using small interfering technique we showed that c-Fos is involved in rhMMP-12-induced IL-8/CXCL8 production. From these results, we conclude that one mechanism, by which MMP-12 induces IL-8/CXCL8 release from the alveolar epithelium, is the EGFR/ERK1/2/AP-1 pathway.