Cell and agonist‐specific regulation of genes for matrix metalloproteinases and their tissue inhibitors by primary glial cells

Abstract

An imbalance in the matrix metalloproteinase (MMP) : tissue inhibitor of MMP (TIMP) ratio may be associated with tissue injury. Here, we studied the regulation of TIMP and MMP gene expression in primary glial cultures to ascertain the factors involved in the regulation of these genes in conditions of inflammatory neuropathology. Astrocytes were found to basally express TIMP-1 and TIMP-3 mRNA while microglia expressed only TIMP-2 mRNA. TIMP-4 mRNA was not detectable in either cell type. Treatment with interferon-a (IFN-a), IFN-c, interleukin-3 (IL-3), IL-6 or tumor necrosis factor-a (TNF-a) did not alter expression of the TIMP genes. However, in astrocytes, but not in microglia, serum, IL-1b or lipopolysaccharide (LPS) evoked a dose-and time-dependent increase in TIMP-1 mRNA and a coincident down-regulation of the TIMP-3 gene. Astrocytes were found to express mRNA constitutively for MMPs -3, -11 and -14. In contrast, microglia expressed only MMP-12 mRNA under basal conditions. IL-1b enhanced MMP-3 mRNA levels while LPS increased the MMP-3, -9, -12, -13 and -14 mRNAs. Our findings reveal that regulatory control of TIMP and MMP gene expression by glial cells is agonist-and cell-type specific, and suggest that innate immune signals govern the temporal and spatial expression patterns of TIMP and MMP genes in neuroinflammatory conditions of the CNS.

Fibronectin- and Vitronectin-Induced Microglial Activation and Matrix Metalloproteinase-9 Expression Is Mediated by Integrins α5β1 and αvβ5

“…Thus, it seems likely that MMP-3 is an important upstream molecule for stimulating microglial activity, first by directly promoting microglial activation and second, by mediating activation of microglial pro-MMP-9. Taken together with our recent finding that MMP-3 is produced specifically by astrocytes, but not microglia, stimulated by LPS or IL-1␤ (86), this implies that within the inflamed CNS, astrocyte production of MMP-3 would be one mechanism leading to activation of microglial pro-MMP-9.…”

Metalloproteinases and Metalloproteinase Inhibitors in Age-Related Diseases

“…It has also been suggested that the effects of LPS on the MMPs expression are due in part to the formation of pro-inflammatory cytokines. TNF-and IL-1 produce a significant increase in the production of MMP-3 and MMP-9 in cultured astrocytes and microglia [302,317]. In LPS-stimulated astrocytes, smaller increases of MMP-10, -12, and -13 were also seen [318].…”

Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia

“…It has been suggested that the effects of LPS on the expression of MMPs are due in part to the formation of proinflammatory cytokines. TNF-α and IL-1β produce a significant increase in the production of MMP-3 and -9 in cultured astrocytes and microglia (Gottschall and Yu, 1995;Kauppinen and Swanson, 2005;Crocker et al, 2006). A recent study found that endothelin-1, which is increased in cerebral ischemia, is a potent inducer of MMP-3 production in primary rat astrocytes (Koyama and Tanaka, 2008).…”