Suppression of matrix metalloproteinase-9 transcription by transforming growth factor-beta is mediated by a nuclear factor-kappaB site

Kenji Ogawa, Feifei Chen, Chenzhong Kuang, Yan Chen
Biochemical Journal 2004 July 15, 381 (Pt 2): 413-22
TGF-beta (transforming growth factor-beta) plays a critical role in modulating the inflammatory response and other biological processes through its regulation of the production of MMPs (matrix metalloproteinases). In both Mono-Mac-6 and RAW264.7 monocyte/macrophage cells, TGF-beta abrogated lipopolysaccharide-induced increases in the enzymic activity and mRNA level of MMP-9. A fragment of the human MMP-9 promoter was used to characterize its regulation by TGF-beta signalling. In RAW264.7 cells, TGF-beta or its downstream signalling protein, Smad3 (Sma- and Mad-related protein 3), inhibited lipopolysaccharide-stimulated promoter activity. The suppressive activity of TGF-beta on the MMP-9 promoter was abrogated by an inhibitory Smad, Smad7. The MMP-9 promoter contains a putative TIE (TGF-beta inhibitory element). However, neither mutation nor deletion of the TIE had any effect on the inhibitory activity of TGF-beta on MMP-9 transcription, indicating that the consensus TIE is not required for this effect of TGF-beta. Analysis using a series of deletion mutants of the MMP-9 promoter revealed that a region containing a consensus NF-kappaB (nuclear factor-kappaB) site is required for the basal activity and TGF-beta-mediated suppression of the promoter. Mutation of the putative NF-kappaB site not only markedly reduced the basal transcriptional activity of the promoter, but also abrogated the responsiveness of the promoter to TGF-beta. In addition, a minimal promoter containing one copy of the NF-kappaB sequence was responsive to TGF-beta treatment. Furthermore, an electrophoretic mobility shift assay was performed with the nuclear extracts from RAW264.7 cells, and it was found that TGF-beta treatment did not disrupt the binding of NF-kappaB p50 and p65 proteins to the NF-kappaB sequence. Taken together, these studies indicate that the NF-kappaB site is indispensable for the suppressive activity of TGF-beta in the regulation of MMP-9 transcription.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"