Astrocyte reactivity to Fas activation is attenuated in TIMP-1 deficient mice, an in vitro study

Crystel Ogier¹ , Rita Creidy¹ , José Boucraut¹ , Paul D Soloway² , Michel Khrestchatisky¹ and Santiago Rivera¹

¹Neurobiologie des Interactions Cellulaires et Neurophysiopathologie (NICN), CNRS UMR 6184. Université de la Méditerranée. Faculté de Médecine de Marseille, IFR Jean Roche. Bd. Pierre Dramard, 13916, Marseille cedex 20, France

²Division of Nutritional Sciences College of Agriculture and Life Sciences, Cornell University 108 Savage Hall Ithaca, NY 14853-6301 USA

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BMC Neuroscience 2005, 6:68doi:10.1186/1471-2202-6-68


Published:	29 November 2005

Abstract

Background

Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a multifunctional secreted protein with pleiotropic actions, including the inhibition of matrix metalloproteinases (MMPs), cell death/survival and growth promoting activities. After inflammatory challenge, the levels of TIMP-1 are highly and selectively upregulated in astrocytes among glial cells, but little is know about its role in these neural cells. We investigated the influence of TIMP-1 null mutation in the reactivity of cultured astrocytes to pro-inflammatory stimuli with TNF-α and anti-Fas antibody.

Results

When compared to WT, mutant astrocytes displayed an overall increased constitutive gelatinase expression and were less responsive to Fas-mediated upregulation of MMP-9, of monocyte chemoattractant protein-1 (MCP-1) and of intercellular cell adhesion molecule-1 (ICAM-1), all markers of astrocyte inflammatory response. In contrast, TNF-α treatment induced all these factors similarly regardless of the astrocyte genotype. The incorporation of ³H-thymidin, a marker of cell proliferation, increased in wild-type (WT) astrocytes after treatment with anti-Fas antibody or recombinant TIMP-1 but not in mutant astrocytes. Finally, lymphocyte chemotaxis was differentially regulated by TNF-α in WT and TIMP-1 deficient astrocytes.

Conclusion

We provide evidence that the alteration of the MMP/TIMP balance in astrocytes influences their reactivity to pro-inflammatory stimuli and that Fas activation modulates the expression of members of the MMP/TIMP axis. We hypothesise that the Fas/FasL transduction pathway and the MMP/TIMP system interact in astrocytes to modulate their inflammatory response to environmental stimuli.