Matrix metalloproteinase (MMP)-1 and MMP-3 induce macrophage MMP-9: Evidence for the role of TNF-α and cyclooxygenase-2

Michel Steenport, K. M Faisal Khan, Baoheng Du, Sarah E Barnhard, Andrew J. Dannenberg, Domenick J. Falcone

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Matrix metalloproteinase (MMP)-9 (gelatinase B) participates in a variety of diverse physiologic and pathologic processes. We recently characterized a cyclooxygenase-2 (COX-2)→PGE2→EP4 receptor axis that regulates macrophage MMP-9 expression. In the present studies, we determined whether MMPs, commonly found in inflamed and neoplastic tissues, regulate this prostanoid-EP receptor axis leading to enhanced MMP-9 expression. Results demonstrate that exposure of murine peritoneal macrophages and RAW264.7 macrophages to MMP-1 (collagenase-1) or MMP-3 (stromelysin-1) lead to a marked increase in COX-2 expression, PGE2 secretion, and subsequent induction of MMP-9 expression. Proteinase-induced MMP-9 expression was blocked in macrophages preincubated with the selective COX-2 inhibitor celecoxib or transfected with COX-2 small interfering RNA (siRNA). Likewise, proteinase-induced MMP-9 was blocked in macrophages preincubated with the EP4 antagonist ONO-AE3-208 or transfected with EP4 siRNA. Exposure of macrophages to MMP-1 and MMP-3 triggered the rapid release of TNF-α, which was blocked by MMP inhibitors. Furthermore, both COX-2 and MMP-9 expression were inhibited in macrophages preincubated with anti-TNF-α IgG or transfected with TNF-α siRNA. Thus, proteinase-induced MMP-9 expression by macrophages is dependent on the release of TNF-α, induction of COX-2 expression, and PGE2 engagement of EP4. The ability of MMP-1 and MMP-3 to regulate macrophage secretion of PGE2 and expression of MMP-9 defines a nexus between MMPs and prostanoids that is likely to play a role in the pathogenesis of chronic inflammatory diseases and cancer. These data also suggest that this nexus is targetable utilizing anti-TNF-α therapies and/or selective EP4 antagonists.

Original languageEnglish (US)
Pages (from-to)8119-8127
Number of pages9
JournalJournal of Immunology
Volume183
Issue number12
DOIs
StatePublished - Dec 15 2009
Externally publishedYes

Fingerprint

Matrix Metalloproteinase 3
Matrix Metalloproteinase 1
Matrix Metalloproteinase 9
Cyclooxygenase 2
Macrophages
Dinoprostone
Small Interfering RNA
Peptide Hydrolases
Celecoxib
Matrix Metalloproteinases
Prostaglandins
Matrix Metalloproteinase Inhibitors
Cyclooxygenase 2 Inhibitors
Peritoneal Macrophages
Pathologic Processes
Chronic Disease

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Matrix metalloproteinase (MMP)-1 and MMP-3 induce macrophage MMP-9 : Evidence for the role of TNF-α and cyclooxygenase-2. / Steenport, Michel; Khan, K. M Faisal; Du, Baoheng; Barnhard, Sarah E; Dannenberg, Andrew J.; Falcone, Domenick J.

In: Journal of Immunology, Vol. 183, No. 12, 15.12.2009, p. 8119-8127.

Research output: Contribution to journalArticle

Steenport, Michel ; Khan, K. M Faisal ; Du, Baoheng ; Barnhard, Sarah E ; Dannenberg, Andrew J. ; Falcone, Domenick J. / Matrix metalloproteinase (MMP)-1 and MMP-3 induce macrophage MMP-9 : Evidence for the role of TNF-α and cyclooxygenase-2. In: Journal of Immunology. 2009 ; Vol. 183, No. 12. pp. 8119-8127.
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AU - Khan, K. M Faisal

AU - Du, Baoheng

AU - Barnhard, Sarah E

AU - Dannenberg, Andrew J.

AU - Falcone, Domenick J.

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