Possible involvements of nuclear factor-kappa B and activator protein-1 in the tumor necrosis factor-alpha-induced upregulation of matrix metalloproteinase-12 in human alveolar epithelial A549 cell line.
Matrix metalloproteinase-12 (MMP-12) has been suggested to play an important role in airway inflammatory diseases. Tumor necrosis factor-alpha (TNF-alpha) 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-alpha 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-alpha in the absence or presence of BMS-345541 (a selective IkappaB 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-kappaB (NF-kappaB) and AP-1 in the MMP-12 mRNA expression induced by TNF-alpha in A549 cells. Both MMP-12 mRNA and protein were upregulated by the treatment with TNF-alpha in time- and concentration-dependent manners. Both BMS-345541 and SP600125 inhibited the upregulation of MMP-12 induced by TNF-alpha. Furthermore, both the depletion of p65 and JNK2 by siRNAs significantly attenuated the upregulation of MMP-12 induced by TNF-alpha. These findings suggest that both NF-kappaB and JNK / AP-1 pathways are important for the MMP-12 upregulation induced by TNF-alpha in A549 cells.
Yu
Yingyan
Y
Department of Pharmacology, School of Pharmacy, Hoshi University, Japan.
Chiba
Yoshihiko
Y
Sakai
Hiroyasu
H
Misawa
Miwa
M
D045744:Cell Line, Tumor; D006801:Humans; D053508:Matrix Metalloproteinase 12 / Q000096:biosynthesis*; D016328:NF-kappa B / Q000096:biosynthesis*; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000201:enzymology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D053508:Matrix Metalloproteinase 12