Matrix metalloproteinase 8 (collagenase 2) induces the expression of interleukins 6 and 8 in breast cancer cells

Sally Thirkettle, Julie Decock, Hugh Arnold, Caroline J. Pennington, Diane M. Jaworski, Dylan R. Edwards

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Matrix metalloproteinase 8 (MMP-8) is a tumor-suppressive protease that cleaves numerous substrates, including matrix proteins and chemokines. In particular, MMP-8 proteolytically activates IL-8 and, thereby, regulates neutrophil chemotaxis in vivo. We explored the effects of expression of either a WT or catalytically inactive (E198A) mutant version of MMP-8 in human breast cancer cell lines. Analysis of serum-free conditioned media from three breast cancer cell lines (MCF-7, SK-BR-3, and MDA-MB-231) expressing WT MMP-8 revealed elevated levels of IL-6 and IL-8. This increase was mirrored at the mRNA level and was dependent on MMP-8 catalytic activity. However, sustained expression of WT MMP-8 by breast cancer cells was non-permissive for long-term growth, as shown by reduced colony formation compared with cells expressing either control vector or E198A mutantMMP-8.In long-term culture of transfected MDA-MB-231 cells, expression of WT but not E198A mutant MMP-8 was lost, with IL-6 and IL-8 levels returning to base line. Rare clonal isolates of MDA-MB-231cells expressing WT MMP-8 were generated, and these showed constitutively high levels of IL-6 and IL-8, although production of the interleukins was no longer dependent upon MMP-8 activity. These studies support a causal connection between MMP-8 activity and the IL-6/IL-8 network, with an acute response to MMP-8 involving induction of the proinflammatory mediators, which may in part serve to compensate for the deleterious effects of MMP-8 on breast cancer cell growth. This axis may be relevant to the recognized ability of MMP-8 to orchestrate the innate immune system in inflammation in vivo.

Original languageEnglish
Pages (from-to)16282-16294
Number of pages13
JournalJournal of Biological Chemistry
Volume288
Issue number23
DOIs
Publication statusPublished - 7 Jun 2013
Externally publishedYes

Fingerprint

Matrix Metalloproteinase 8
Interleukin-8
Interleukin-6
Cells
Breast Neoplasms
Cell Line
Immune system
Interleukins
Serum-Free Culture Media
Cell growth
Chemotaxis
Conditioned Culture Medium
Growth
Chemokines

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Matrix metalloproteinase 8 (collagenase 2) induces the expression of interleukins 6 and 8 in breast cancer cells. / Thirkettle, Sally; Decock, Julie; Arnold, Hugh; Pennington, Caroline J.; Jaworski, Diane M.; Edwards, Dylan R.

In: Journal of Biological Chemistry, Vol. 288, No. 23, 07.06.2013, p. 16282-16294.

Research output: Contribution to journalArticle

Thirkettle, Sally ; Decock, Julie ; Arnold, Hugh ; Pennington, Caroline J. ; Jaworski, Diane M. ; Edwards, Dylan R. / Matrix metalloproteinase 8 (collagenase 2) induces the expression of interleukins 6 and 8 in breast cancer cells. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 23. pp. 16282-16294.
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