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. 2003 Sep;58(9):778–783. doi: 10.1136/thorax.58.9.778

Inhibition of MMP-9 expression by PPARγ activators in human bronchial epithelial cells

M Hetzel 1, D Walcher 1, M Grub 1, H Bach 1, V Hombach 1, N Marx 1
PMCID: PMC1746807  PMID: 12947137

Abstract

Methods: A study was undertaken to examine whether activators of the nuclear transcription factor peroxisome proliferator activated receptor gamma (PPARγ) might modulate MMP-9 expression in two different bronchial epithelial cell lines.

Results: PPARγ was expressed and was functionally active in NL20 and BEAS cells. Activation of PPARγ by rosiglitazone or pioglitazone significantly reduced TNF-α and PMA induced MMP-9 gelatinolytic activity in a concentration dependent manner in both cell lines, but did not alter the expression of tissue inhibitor of MMPs type 1 (TIMP-1), the local inhibitor of MMP-9. Northern blot analysis revealed a decrease in MMP-9 mRNA expression following treatment with PPARγ which resulted from the inhibition of NF-κB activation in these cells, as determined by transient transfection assays and electromobility shift assays.

Conclusion: Activation of PPARγ in human bronchial epithelial cells limits the expression of matrix degrading MMP-9. This might have therapeutic applications in chronic inflammatory processes of the respiratory system.

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Selected References

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  1. Benayoun L., Letuve S., Druilhe A., Boczkowski J., Dombret M. C., Mechighel P., Megret J., Leseche G., Aubier M., Pretolani M. Regulation of peroxisome proliferator-activated receptor gamma expression in human asthmatic airways: relationship with proliferation, apoptosis, and airway remodeling. Am J Respir Crit Care Med. 2001 Oct 15;164(8 Pt 1):1487–1494. doi: 10.1164/ajrccm.164.8.2101070. [DOI] [PubMed] [Google Scholar]
  2. Busse W., Elias J., Sheppard D., Banks-Schlegel S. Airway remodeling and repair. Am J Respir Crit Care Med. 1999 Sep;160(3):1035–1042. doi: 10.1164/ajrccm.160.3.9902064. [DOI] [PubMed] [Google Scholar]
  3. Chawla A., Barak Y., Nagy L., Liao D., Tontonoz P., Evans R. M. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med. 2001 Jan;7(1):48–52. doi: 10.1038/83336. [DOI] [PubMed] [Google Scholar]
  4. Clark Robert B. The role of PPARs in inflammation and immunity. J Leukoc Biol. 2002 Mar;71(3):388–400. [PubMed] [Google Scholar]
  5. Dahlen B., Shute J., Howarth P. Immunohistochemical localisation of the matrix metalloproteinases MMP-3 and MMP-9 within the airways in asthma. Thorax. 1999 Jul;54(7):590–596. doi: 10.1136/thx.54.7.590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Elias J. A., Zhu Z., Chupp G., Homer R. J. Airway remodeling in asthma. J Clin Invest. 1999 Oct;104(8):1001–1006. doi: 10.1172/JCI8124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Inoue K., Kawahito Y., Tsubouchi Y., Yamada R., Kohno M., Hosokawa Y., Katoh D., Bishop-Bailey D., Hla T., Sano H. Expression of peroxisome proliferator-activated receptor (PPAR)-gamma in human lung cancer. Anticancer Res. 2001 Jul-Aug;21(4A):2471–2476. [PubMed] [Google Scholar]
  8. Jiang C., Ting A. T., Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998 Jan 1;391(6662):82–86. doi: 10.1038/34184. [DOI] [PubMed] [Google Scholar]
  9. Kim J. B., Spiegelman B. M. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev. 1996 May 1;10(9):1096–1107. doi: 10.1101/gad.10.9.1096. [DOI] [PubMed] [Google Scholar]
  10. Kliewer S. A., Lenhard J. M., Willson T. M., Patel I., Morris D. C., Lehmann J. M. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell. 1995 Dec 1;83(5):813–819. doi: 10.1016/0092-8674(95)90194-9. [DOI] [PubMed] [Google Scholar]
  11. Lehmann J. M., Moore L. B., Smith-Oliver T. A., Wilkison W. O., Willson T. M., Kliewer S. A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995 Jun 2;270(22):12953–12956. doi: 10.1074/jbc.270.22.12953. [DOI] [PubMed] [Google Scholar]
  12. Marx N., Libby P., Plutzky J. Peroxisome proliferator-activated receptors (PPARs) and their role in the vessel wall: possible mediators of cardiovascular risk? J Cardiovasc Risk. 2001 Aug;8(4):203–210. doi: 10.1177/174182670100800404. [DOI] [PubMed] [Google Scholar]
  13. Marx N., Mach F., Sauty A., Leung J. H., Sarafi M. N., Ransohoff R. M., Libby P., Plutzky J., Luster A. D. Peroxisome proliferator-activated receptor-gamma activators inhibit IFN-gamma-induced expression of the T cell-active CXC chemokines IP-10, Mig, and I-TAC in human endothelial cells. J Immunol. 2000 Jun 15;164(12):6503–6508. doi: 10.4049/jimmunol.164.12.6503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Marx N., Schönbeck U., Lazar M. A., Libby P., Plutzky J. Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res. 1998 Nov 30;83(11):1097–1103. doi: 10.1161/01.res.83.11.1097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Marx N., Sukhova G., Murphy C., Libby P., Plutzky J. Macrophages in human atheroma contain PPARgamma: differentiation-dependent peroxisomal proliferator-activated receptor gamma(PPARgamma) expression and reduction of MMP-9 activity through PPARgamma activation in mononuclear phagocytes in vitro. Am J Pathol. 1998 Jul;153(1):17–23. doi: 10.1016/s0002-9440(10)65540-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Mautino G., Oliver N., Chanez P., Bousquet J., Capony F. Increased release of matrix metalloproteinase-9 in bronchoalveolar lavage fluid and by alveolar macrophages of asthmatics. Am J Respir Cell Mol Biol. 1997 Nov;17(5):583–591. doi: 10.1165/ajrcmb.17.5.2562. [DOI] [PubMed] [Google Scholar]
  17. Ohno I., Ohtani H., Nitta Y., Suzuki J., Hoshi H., Honma M., Isoyama S., Tanno Y., Tamura G., Yamauchi K. Eosinophils as a source of matrix metalloproteinase-9 in asthmatic airway inflammation. Am J Respir Cell Mol Biol. 1997 Mar;16(3):212–219. doi: 10.1165/ajrcmb.16.3.9070604. [DOI] [PubMed] [Google Scholar]
  18. Plosker G. L., Faulds D. Troglitazone: a review of its use in the management of type 2 diabetes mellitus. Drugs. 1999 Mar;57(3):409–438. doi: 10.2165/00003495-199957030-00014. [DOI] [PubMed] [Google Scholar]
  19. Ricote M., Li A. C., Willson T. M., Kelly C. J., Glass C. K. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998 Jan 1;391(6662):79–82. doi: 10.1038/34178. [DOI] [PubMed] [Google Scholar]
  20. Sakamoto J., Kimura H., Moriyama S., Odaka H., Momose Y., Sugiyama Y., Sawada H. Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem Biophys Res Commun. 2000 Nov 30;278(3):704–711. doi: 10.1006/bbrc.2000.3868. [DOI] [PubMed] [Google Scholar]
  21. Schoonjans K., Martin G., Staels B., Auwerx J. Peroxisome proliferator-activated receptors, orphans with ligands and functions. Curr Opin Lipidol. 1997 Jun;8(3):159–166. doi: 10.1097/00041433-199706000-00006. [DOI] [PubMed] [Google Scholar]
  22. Schoonjans K., Staels B., Auwerx J. The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta. 1996 Jul 26;1302(2):93–109. doi: 10.1016/0005-2760(96)00066-5. [DOI] [PubMed] [Google Scholar]
  23. Tsubouchi Y., Sano H., Kawahito Y., Mukai S., Yamada R., Kohno M., Inoue K., Hla T., Kondo M. Inhibition of human lung cancer cell growth by the peroxisome proliferator-activated receptor-gamma agonists through induction of apoptosis. Biochem Biophys Res Commun. 2000 Apr 13;270(2):400–405. doi: 10.1006/bbrc.2000.2436. [DOI] [PubMed] [Google Scholar]
  24. Yao P. M., Buhler J. M., d'Ortho M. P., Lebargy F., Delclaux C., Harf A., Lafuma C. Expression of matrix metalloproteinase gelatinases A and B by cultured epithelial cells from human bronchial explants. J Biol Chem. 1996 Jun 28;271(26):15580–15589. doi: 10.1074/jbc.271.26.15580. [DOI] [PubMed] [Google Scholar]

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