Cargando…

Interleukin-4 inhibition of interleukin-1-induced expression of matrix metalloproteinase-3 (MMP-3) is independent of lipoxygenase and PPARγ activation in human gingival fibroblasts

BACKGROUND: Interleukin 4 (IL-4) has been shown to suppress interleukin-1 (IL-1) induced expression of matrix metalloproteinase-3 (MMP-3) in human synovial and gingival fibroblasts, but the mechanism of suppression has not been determined. Activators of peroxisome proliferator-activated receptor-γ (...

Descripción completa

Detalles Bibliográficos
Autores principales: Stewart, Denise, Javadi, Masoud, Chambers, Mariah, Gunsolly, Chad, Gorski, Grzegorz, Borghaei, Ruth C
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810308/
https://www.ncbi.nlm.nih.gov/pubmed/17319946
http://dx.doi.org/10.1186/1471-2199-8-12
_version_ 1782132574457430016
author Stewart, Denise
Javadi, Masoud
Chambers, Mariah
Gunsolly, Chad
Gorski, Grzegorz
Borghaei, Ruth C
author_facet Stewart, Denise
Javadi, Masoud
Chambers, Mariah
Gunsolly, Chad
Gorski, Grzegorz
Borghaei, Ruth C
author_sort Stewart, Denise
collection PubMed
description BACKGROUND: Interleukin 4 (IL-4) has been shown to suppress interleukin-1 (IL-1) induced expression of matrix metalloproteinase-3 (MMP-3) in human synovial and gingival fibroblasts, but the mechanism of suppression has not been determined. Activators of peroxisome proliferator-activated receptor-γ (PPARγ) have been shown to inhibit cytokine induced expression of MMPs in other cell types, and IL-4 has been shown to activate PPARγ by stimulating production of ligands through the lipoxygenase pathway. It has been suggested that PPARγ may inhibit expression of MMPs by competing with transcription factor AP-1 for binding to a putative composite binding element in the promoters. The objective of this study was to determine whether the suppressive effects of IL-4 on the IL-1 induced expression of MMP-3 involve activation of lipoxygenase and/or PPARγ. RESULTS: Western blotting revealed the presence of PPARγ in nuclear extract of HGF. IL-1 induced binding of nuclear extract to the putative composite PPRE/AP-1 site was diminished in the presence of pioglitazone, but there was no evidence of any change in the composition of the retarded complexes, and no evidence of PPARγ binding to this site. Nordihydroguaiaretic acid (NDGA), a non-selective lipoxygenase inhibitor, and MK886, a specific inhibitor of 5-lipoxygenase, induced MMP-3 expression synergistically with IL-1. However IL-4 was still able to inhibit MMP-3 expression in the presence of NDGA or MK886 and IL-1. Activation of PPARγ with pioglitazone not only failed to inhibit IL-1 induced expression of MMP-3 mRNA, but rather super-induced MMP-3 in the presence of IL-1. PPARγ antagonist GW9662 failed to abolish the suppressive effects of IL-4. Another PPARγ activator, 15-deoxy-Delta12,14prostaglandin J2 (15dPGJ2), also super-induced MMP-3 mRNA, and this was due at least in part to increased transcription. CONCLUSION: IL-4 suppression of IL-1-induced MMP-3 expression in HGF is independent of lipoxygenase activity and activation of PPARγ. Super-induction of MMP-3 by pioglitazone may have important implications for patients using pioglitazone to treat type II diabetes in the presence of chronic inflammation.
format Text
id pubmed-1810308
institution National Center for Biotechnology Information
language English
publishDate 2007
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-18103082007-03-06 Interleukin-4 inhibition of interleukin-1-induced expression of matrix metalloproteinase-3 (MMP-3) is independent of lipoxygenase and PPARγ activation in human gingival fibroblasts Stewart, Denise Javadi, Masoud Chambers, Mariah Gunsolly, Chad Gorski, Grzegorz Borghaei, Ruth C BMC Mol Biol Research Article BACKGROUND: Interleukin 4 (IL-4) has been shown to suppress interleukin-1 (IL-1) induced expression of matrix metalloproteinase-3 (MMP-3) in human synovial and gingival fibroblasts, but the mechanism of suppression has not been determined. Activators of peroxisome proliferator-activated receptor-γ (PPARγ) have been shown to inhibit cytokine induced expression of MMPs in other cell types, and IL-4 has been shown to activate PPARγ by stimulating production of ligands through the lipoxygenase pathway. It has been suggested that PPARγ may inhibit expression of MMPs by competing with transcription factor AP-1 for binding to a putative composite binding element in the promoters. The objective of this study was to determine whether the suppressive effects of IL-4 on the IL-1 induced expression of MMP-3 involve activation of lipoxygenase and/or PPARγ. RESULTS: Western blotting revealed the presence of PPARγ in nuclear extract of HGF. IL-1 induced binding of nuclear extract to the putative composite PPRE/AP-1 site was diminished in the presence of pioglitazone, but there was no evidence of any change in the composition of the retarded complexes, and no evidence of PPARγ binding to this site. Nordihydroguaiaretic acid (NDGA), a non-selective lipoxygenase inhibitor, and MK886, a specific inhibitor of 5-lipoxygenase, induced MMP-3 expression synergistically with IL-1. However IL-4 was still able to inhibit MMP-3 expression in the presence of NDGA or MK886 and IL-1. Activation of PPARγ with pioglitazone not only failed to inhibit IL-1 induced expression of MMP-3 mRNA, but rather super-induced MMP-3 in the presence of IL-1. PPARγ antagonist GW9662 failed to abolish the suppressive effects of IL-4. Another PPARγ activator, 15-deoxy-Delta12,14prostaglandin J2 (15dPGJ2), also super-induced MMP-3 mRNA, and this was due at least in part to increased transcription. CONCLUSION: IL-4 suppression of IL-1-induced MMP-3 expression in HGF is independent of lipoxygenase activity and activation of PPARγ. Super-induction of MMP-3 by pioglitazone may have important implications for patients using pioglitazone to treat type II diabetes in the presence of chronic inflammation. BioMed Central 2007-02-23 /pmc/articles/PMC1810308/ /pubmed/17319946 http://dx.doi.org/10.1186/1471-2199-8-12 Text en Copyright © 2007 Stewart et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Stewart, Denise
Javadi, Masoud
Chambers, Mariah
Gunsolly, Chad
Gorski, Grzegorz
Borghaei, Ruth C
Interleukin-4 inhibition of interleukin-1-induced expression of matrix metalloproteinase-3 (MMP-3) is independent of lipoxygenase and PPARγ activation in human gingival fibroblasts
title Interleukin-4 inhibition of interleukin-1-induced expression of matrix metalloproteinase-3 (MMP-3) is independent of lipoxygenase and PPARγ activation in human gingival fibroblasts
title_full Interleukin-4 inhibition of interleukin-1-induced expression of matrix metalloproteinase-3 (MMP-3) is independent of lipoxygenase and PPARγ activation in human gingival fibroblasts
title_fullStr Interleukin-4 inhibition of interleukin-1-induced expression of matrix metalloproteinase-3 (MMP-3) is independent of lipoxygenase and PPARγ activation in human gingival fibroblasts
title_full_unstemmed Interleukin-4 inhibition of interleukin-1-induced expression of matrix metalloproteinase-3 (MMP-3) is independent of lipoxygenase and PPARγ activation in human gingival fibroblasts
title_short Interleukin-4 inhibition of interleukin-1-induced expression of matrix metalloproteinase-3 (MMP-3) is independent of lipoxygenase and PPARγ activation in human gingival fibroblasts
title_sort interleukin-4 inhibition of interleukin-1-induced expression of matrix metalloproteinase-3 (mmp-3) is independent of lipoxygenase and pparγ activation in human gingival fibroblasts
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810308/
https://www.ncbi.nlm.nih.gov/pubmed/17319946
http://dx.doi.org/10.1186/1471-2199-8-12
work_keys_str_mv AT stewartdenise interleukin4inhibitionofinterleukin1inducedexpressionofmatrixmetalloproteinase3mmp3isindependentoflipoxygenaseandppargactivationinhumangingivalfibroblasts
AT javadimasoud interleukin4inhibitionofinterleukin1inducedexpressionofmatrixmetalloproteinase3mmp3isindependentoflipoxygenaseandppargactivationinhumangingivalfibroblasts
AT chambersmariah interleukin4inhibitionofinterleukin1inducedexpressionofmatrixmetalloproteinase3mmp3isindependentoflipoxygenaseandppargactivationinhumangingivalfibroblasts
AT gunsollychad interleukin4inhibitionofinterleukin1inducedexpressionofmatrixmetalloproteinase3mmp3isindependentoflipoxygenaseandppargactivationinhumangingivalfibroblasts
AT gorskigrzegorz interleukin4inhibitionofinterleukin1inducedexpressionofmatrixmetalloproteinase3mmp3isindependentoflipoxygenaseandppargactivationinhumangingivalfibroblasts
AT borghaeiruthc interleukin4inhibitionofinterleukin1inducedexpressionofmatrixmetalloproteinase3mmp3isindependentoflipoxygenaseandppargactivationinhumangingivalfibroblasts