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Alexandre Denoyer, David Godefroy, Julie Frugier, Françoise Brignole-Baudouin, William Rostène, Christophe Baudouin; The Chemokine CXCL12 Cleaved Form SDF-1(5-67) is Involved in the Trabecular Cell Apoptosis via CXCR3. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4655.
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To study the role of CXCL12 (SDF-1) and its cleaved form SDF-1(5-67) in the trabecular cell viability.
Expression of CXC12 and both CXCR3 and CXCR4 receptors was studied under various experimental conditions in human glaucomatous trabecular meshwork (TM) samples and a trabecular cell (TC) line using RT-PCR, immunofluorescence, flow cytometry (FCM), and ELISA. A specific anti-SDF-1(5-67) antibody was used to detect the TC production of this truncated form of CXCL12 by Western Blot. CXCL12 and SDF-1(5-67) effects on the TC viability were studied by microplate cytofluorometry and FCM in a TC model of induced apoptosis. Non-peptide specific antagonists of chemokine receptors CXCR3 and CXCR4 were tested in order to determine the receptor involved.
CXCL12, CXCR3 and CXCR4 were detected in both human glaucomatous TM tissue and TC line. In vitro the expression of the chemokine and of both receptors was differently enhanced by TNF-a and TGF-b2. The basal TC production of SDF-1(5-67) was also enhanced by both cytokines and reduced by MMP inhibitors (P<0.05). CXCL12 significantly promoted TC survival via its binding to CXCR4, whereas SDF-1(5-67) induced apoptosis in a dose-dependent manner via CXCR3 and caspase 3 activation.
We demonstrate that CXCL12 and its truncated form SDF-1(5-67) regulate the TC survival through two different chemokine receptors. Such a balance is regulated by cytokines and MMPs previously detected in the glaucomatous TM. SDF-1(5-67) and CXCR3 could be involved in pathological changes observed in the TM in glaucoma.
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