Matrix metalloproteinase-12 (MMP-12) has been suggested to play an important role in airway inflammatory diseases. Tumor necrosis factor-α (TNF-α) is known to cause an upregulation of MMP-12 via an activation of activator protein-1 (AP-1) in monocytes. In the present study, we investigated the effect of TNF-α on the expressions of MMP-12 in airway epithelial cells, one of the sources of MMP-12 in the airway, and its underlying mechanism. MMP-12 mRNA and protein expressions induced by TNF-α in the absence or presence of BMS-345541 (a selective IκB kinase inhibitor) or SP600125 [a selective c-Jun N-terminal kinase (JNK) inhibitor] were measured by quantitative real-time PCR and Western blotting, respectively. Furthermore, siRNAs for p65 and JNK2 were used to confirm the involvements of nuclear factor-κB (NF-κB) and AP-1 in the MMP-12 mRNA expression induced by TNF-α in A549 cells. Both MMP-12 mRNA and protein were upregulated by the treatment with TNF-α in time- and concentration-dependent manners. Both BMS-345541 and SP600125 inhibited the upregulation of MMP-12 induced by TNF-α. Furthermore, both the depletion of p65 and JNK2 by siRNAs significantly attenuated the upregulation of MMP-12 induced by TNF-α. These findings suggest that both NF-κB and JNK / AP-1 pathways are important for the MMP-12 upregulation induced by TNF-α in A549 cells.