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


CONCLUSIONS
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.
Ogier
Crystel
C
Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, CNRS UMR 6184, Université de la Méditerranée, Faculté de Médecine de Marseille, IFR Jean Roche, Bd, Pierre Dramard, 13916, Marseille cedex 20, France. ogier.c@jean-roche.univ-mrs.fr
Creidy
Rita
R
Boucraut
José
J
Soloway
Paul D
PD
Khrestchatisky
Michel
M
Rivera
Santiago
S
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000009:adverse effects; D001253:Astrocytes / Q000201:enzymology / Q000502:physiology*; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008214:Lymphocytes / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013936:Thymidine / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000172:deficiency*; D014316:Tritium / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects; D019014:fas Receptor
D000906:Antibodies; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C491899:Fas protein, mouse; D005904:Glial Fibrillary Acidic Protein; D018124:Receptors, Tumor Necrosis Factor; D013778:Tetrazolium Salts; D013844:Thiazoles; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D014316:Tritium; D018799:Intercellular Adhesion Molecule-1; D020780:Matrix Metalloproteinase 9; C022616:thiazolyl blue; D013936:Thymidine