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

Crystel Ogier (1) , Rita Creidy (1) , José Boucraut (1) , Paul D Soloway (2) , Michel Khrestchatisky (1) , Santiago Rivera (1)

1 NICN - Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN
2 Cornell University [New York]

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-alpha 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-alpha 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-alpha 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.

Domaines: Neurobiologie

Crystel Ogier, Rita Creidy, José Boucraut, Paul D Soloway, Michel Khrestchatisky, et al.. Astrocyte reactivity to Fas activation is attenuated in TIMP-1 deficient mice, an in vitro study. BMC Neuroscience, 2005, 6 (1), pp.68. ⟨10.1186/1471-2202-6-68⟩. ⟨hal-00092828⟩