Artikel
Glioma-induced Toll like receptors (TLR) signaling in microglia promotes parenchymal MT1-MMP expression and tumor expansion in vivo
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Veröffentlicht: | 16. September 2010 |
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Gliederung
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Objective: We have shown previously that membrane type 1 metalloprotease (MT1-MMP) is upregulated in glioma associated microglia, but not in the glioma cells and that a glioma released factor is stimulating via p38 MAPK overexpression of MT1-MMP in microglia. Now, we investigate with a novel glioma experimental model the possible mediators in microglial expression of MT1-MMP.
Methods: We used immunohistochemistry, in vivo mouse glioma model, 2-photon time lapse microscopy in organotypical brain slice cultures, PCR, and Western Blot in cell culture experiments to demonstrate reduced tumor expansion after interfering with TLR signaling in microglia.
Results: Glioma-released factors trigger the expression and activity of MT1-MMP via microglial TLR and the p38 MAPK pathway since deletion of the TLR adapter protein MyD88 or p38 inhibition prevented MT1-MMP expression and activity in cultured microglial cells. Microglial MT1-MMP in turn activates glioma derived pro-matrix metalloproteinase-2 (pro-MMP-2) and promotes glioma expansion, as shown in an ex vivo model using MT1-MMP deficient brain tissue and a microglia depletion paradigm. Finally, both MyD88-deficiency or microglia depletion largely attenuated glioma expansion in two independent in vivo models.
Conclusions: A glioma released factor is stimulating via TLR's the p38 MAPK overexpression of MT1-MMP, which in turn overproduces active MMP-2.