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Jun Yamada, Kenichi Kimura, Atsushi Mukai, Junji Hamuro, Shigeru Kinoshita; The role of IL-6 and TNF-alfa in generating the vicious inflammatory cycle between macrophages and retinal pigment epithelium in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3447.
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The interaction between macrophages (Mps) and retinal pigment epithelium cells (RPE) reportedly plays an important role in exacerbating age-related macular degeneration (AMD). Oxidized (Ox) low-density lipoprotein (LDL) contributes to the pathogenesis of AMD, and the presence of a high concentration of transforming growth factor beta 2 (TGF-β 2) in the eye may enhance the development of AMD. The purpose of this present study was to determine the cytokine network comprising the vicious inflammatory cycle in order to explore the possibility of developing new strategies for the prevention of AMD.
C57BL6-derived primary RPE (mRPE) and adherent peritoneal Mps (AdPC) were prepared. The mRPE and AdPC were co-cultured, and the produced monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) in supernatants were analyzed by ELIZA assay. LDL (50 µg/ml), ox-LDL (50 µg/ml), or TGF-β 2 (10 ng/ml) stimulation were performed to determine the synergistic effect for enhancement of this cycle. Tumor necrosis factor alpha (TNF-α) or IL-6 was neutralized to determine the main factor composing their vicious cycle.
The mRPE/AdPC co-culture significantly produced MCP-1 (16.2 ng/ml, > x100), IL-6 (3.1 ng/ml, > x100), and VEGF (1034 pg/ml, > x2) than solely mRPE or AdPC culture. The anti-TNF-α Ab neutralizing significantly suppressed MCP-1 (7.8 ng/ml), IL-6 (0.51 ng/ml), and VEGF (420 pg/ml) production, and anti-IL-6 Ab, and anti-gp130 Ab neutralizing significantly suppressed MCP-1 (10.9 and 10.1 ng/ml, respectively) and VEGF (399 and 451 pg/ml, respectively) production. LDL stimulation did not enhance MCP-1 and VEGF, but did enhance IL-6 production. Ox-LDL enhanced IL-6 and VEGF production much more than LDL stimulation, but decreased MCP-1 production. TGF-β also had a synergistic effect on the production of MCP-1, IL-6, and VEGF from mRPE.
The findings of this study show that TNF-α and IL-6 constitute the vicious inflammatory cycle between RPE and Mps. Ox-LDL and TGF-β are able to enhance this cycle and might enhance the development of the early stage of AMD. Since Mps are the main source of TNF-α production, selective treatment of TNF-α produced by Mps is a possible new strategy for preventing the development of AMD.
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