Gene interactions and pathways from curated databases and text-mining
Toxicol Appl Pharmacol 2008, PMID: 18336852

Tumor necrosis factor-alpha induces MMP-9 expression via p42/p44 MAPK, JNK, and nuclear factor-kappaB in A549 cells.

Lin, Chih-Chung; Tseng, Hsiao-Wei; Hsieh, Hsi-Lung; Lee, Chiang-Wen; Wu, Cheng-Ying; Cheng, Ching-Yi; Yang, Chuen-Mao

Matrix metalloproteinases (MMPs), in particular MMP-9, have been shown to be induced by cytokines including tumor necrosis factor-alpha (TNF-alpha) and contributes to airway inflammation. However, the mechanisms underlying MMP-9 expression induced by TNF-alpha in human A549 cells remain unclear. Here, we showed that TNF-alpha induced production of MMP-9 protein and mRNA is determined by zymographic, Western blotting, RT-PCR and ELISA assay, which were attenuated by inhibitors of MEK1/2 (U0126), JNK (SP600125), and NF-kappaB (helenalin), and transfection with dominant negative mutants of ERK2 (DeltaERK) and JNK (DeltaJNK), and siRNAs for MEK1, p42 and JNK2. TNF-alpha-stimulated phosphorylation of p42/p44 MAPK and JNK were attenuated by pretreatment with the inhibitors U0126 and SP600125 or transfection with dominant negative mutants of DeltaERK and DeltaJNK. Furthermore, the involvement of NF-kappaB in TNF-alpha-induced MMP-9 production was consistent with that TNF-alpha-stimulated degradation of IkappaB-alpha and translocation of NF-kappaB into the nucleus which were blocked by helenalin, but not by U0126 and SP600125, revealed by immunofluorescence staining. The regulation of MMP-9 gene transcription by MAPKs and NF-kappaB was further confirmed by gene luciferase activity assay. MMP-9 promoter activity was enhanced by TNF-alpha in A549 cells transfected with wild-type MMP-9-Luc, which was inhibited by helenalin, U0126, or SP600125. In contrast, TNF-alpha-stimulated MMP-9 luciferase activity was totally lost in cells transfected with mutant-NF-kappaB MMP-9-luc. Moreover, pretreatment with actinomycin D and cycloheximide attenuated TNF-alpha-induced MMP-9 expression. These results suggest that in A549 cells, phosphorylation of p42/p44 MAPK, JNK, and transactivation of NF-kappaB are essential for TNF-alpha-induced MMP-9 gene expression.

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Text Mining Data

Tumor necrosis factor-alpha → MMP-9: " Tumor necrosis factor-alpha induces MMP-9 expression via p42/p44 MAPK, JNK, and nuclear factor-kappaB in A549 cells "

MMP-9 → TNF-alpha: " However, the mechanisms underlying MMP-9 expression induced by TNF-alpha in human A549 cells remain unclear "

TNF-alpha → MMP-9: " Here, we showed that TNF-alpha induced production of MMP-9 protein and mRNA is determined by zymographic, Western blotting, RT-PCR and ELISA assay, which were attenuated by inhibitors of MEK1/2 ( U0126 ), JNK ( SP600125 ), and NF-kappaB ( helenalin ), and transfection with dominant negative mutants of ERK2 ( DeltaERK ) and JNK ( DeltaJNK ), and siRNAs for MEK1, p42 and JNK2 "

MAPK → TNF-alpha: " TNF-alpha stimulated phosphorylation of p42/p44 MAPK and JNK were attenuated by pretreatment with the inhibitors U0126 and SP600125 or transfection with dominant negative mutants of DeltaERK and DeltaJNK "

MMP-9 → TNF-alpha: " Furthermore, the involvement of NF-kappaB in TNF-alpha induced MMP-9 production was consistent with that TNF-alpha stimulated degradation of IkappaB-alpha and translocation of NF-kappaB into the nucleus which were blocked by helenalin, but not by U0126 and SP600125, revealed by immunofluorescence staining "

NF-kappaB → TNF-alpha: " Furthermore, the involvement of NF-kappaB in TNF-alpha induced MMP-9 production was consistent with that TNF-alpha stimulated degradation of IkappaB-alpha and translocation of NF-kappaB into the nucleus which were blocked by helenalin, but not by U0126 and SP600125, revealed by immunofluorescence staining "

IkappaB-alpha → TNF-alpha: " Furthermore, the involvement of NF-kappaB in TNF-alpha induced MMP-9 production was consistent with that TNF-alpha stimulated degradation of IkappaB-alpha and translocation of NF-kappaB into the nucleus which were blocked by helenalin, but not by U0126 and SP600125, revealed by immunofluorescence staining "

MMP-9 — NF-kappaB: " Furthermore, the involvement of NF-kappaB in TNF-alpha induced MMP-9 production was consistent with that TNF-alpha stimulated degradation of IkappaB-alpha and translocation of NF-kappaB into the nucleus which were blocked by helenalin, but not by U0126 and SP600125, revealed by immunofluorescence staining "

MMP-9 — NF-kappaB: " The regulation of MMP-9 gene transcription by MAPKs and NF-kappaB was further confirmed by gene luciferase activity assay "

MMP-9 → TNF-alpha: " MMP-9 promoter activity was enhanced by TNF-alpha in A549 cells transfected with wild-type MMP-9-Luc, which was inhibited by helenalin, U0126, or SP600125 "

MMP-9 → TNF-alpha: " In contrast, TNF-alpha stimulated MMP-9 luciferase activity was totally lost in cells transfected with mutant-NF-kappaB MMP-9-luc "

MMP-9 → TNF-alpha: " Moreover, pretreatment with actinomycin D and cycloheximide attenuated TNF-alpha induced MMP-9 expression "

MMP-9 → TNF-alpha: " These results suggest that in A549 cells, phosphorylation of p42/p44 MAPK, JNK, and transactivation of NF-kappaB are essential for TNF-alpha induced MMP-9 gene expression "

MMP-9 → p42/p44: " These results suggest that in A549 cells, phosphorylation of p42/p44 MAPK, JNK, and transactivation of NF-kappaB are essential for TNF-alpha induced MMP-9 gene expression "

MMP-9 → MAPK: " These results suggest that in A549 cells, phosphorylation of p42/p44 MAPK , JNK, and transactivation of NF-kappaB are essential for TNF-alpha induced MMP-9 gene expression "

Manually curated Databases

No curated data.