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and IFN-
1
Departments of
*
Cell Biology,
Pathology, and
Biochemistry and Molecular Genetics, University of Alabama, Birmingham, AL 35294; and
§
Department of Molecular Biology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105
Matrix metalloproteinases (MMPs) are a family of zinc-dependent
endopeptidases that function in the turnover of extracellular matrix
components during development. In addition, MMPs also contribute to
pathological conditions associated with inflammation, angiogenesis, and
tumor invasion. A 72-kDa type IV collagenase, also referred to as
gelatinase A or MMP-2, has been proposed to potentiate the invasion and
metastasis of malignant tumors. In particular, MMP-2 activity has been
shown to constitute an important component of human astroglioma
invasion. We investigated the influence of various cytokines, both
proinflammatory and immunosuppressive, on MMP-2 gene expression in two
human astroglioma cell lines (U251-MG and CRT). Our results indicate
that the cell lines constitutively express high levels of MMP-2 mRNA,
protein, and bioactivity as assessed by ribonuclease protection assay,
immunoblotting, and zymography assays, respectively. The
proinflammatory cytokines TNF-
and IFN-
individually can inhibit
constitutive MMP-2 expression, and function in an additive manner for
near-complete inhibition of MMP-2 expression. Inhibition of MMP-2 mRNA
levels by TNF- and IFN- is not due to destabilization of the
MMP-2 message; rather, inhibition is mediated at the transcriptional
level. Furthermore, TNF-/IFN- inhibition of MMP-2 expression
results in decreased invasiveness of the human astroglioma cells
through an extracellular matrix. These results raise the possibility
that TNF- and IFN- may have beneficial effects in attenuating
astroglioma invasive properties.
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