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C. N. Nagineni, C. Vijayasarathy, B. Detrick, J. J. Hooks; Expression of CCR-3 Ligands, RANTES, MCP-3 and Eotaxins is Differentially Regulated in Human Retinal Pigment Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6163.
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Chemokine receptor-3 (CCR-3) was shown to play a critical role in choroidal neovascularization (CNV) in age related macular degeneration (AMD). Retinal pigment epithelium (RPE) is one of the key tissues in the pathogenesis of AMD. Therefore, we evaluated the expression of CCR-3 ligands RANTES (CCL-5), MCP-3 (CCL-7) and Eotaxins 1,2,3 (CCL-11, 24, 26) by human RPE cells (HRPE).
Primary cultures of HRPE derived from adult donor eyes were used. Confluent cultures grown in 24 well plates were treated with various cytokines and growth factors in serum free medium for 24 h. Levels of secreted CCL-5, -7, -11, -24 and -26 in the culture supernatants were determined by ELISA.
HRPE cells did not secrete CCL- 5, -7, -11, -24 and -26 constitutively or in the presence of IL-2, -5, -6, -8, -10, -11, -12 -13 or -18 and many growth factors. CCL-5 secretion was induced by TNF-α (767 pg/ml) and IL-1β (477 pg/ml) but not by IFN-γ. The presence of IFN-γ significantly enhanced the secretion (3044 pg/ml) of CCL-5. CCL-7 secretion was induced by IFN-γ (483 pg/ml), TNF-α (1572 pg/ml) and IL-1β (2573 pg/ml). TNF-α, IL-1β and IFN-γ alone or together failed to induce CCL-11, -24 and -26 secretions. CCL-11 secretion, barely detectable in IL-4 treated HRPE, was enhanced in the presence of IL-4 +TNF-α (9 pg/ml), IL-4+IL-1β (8 pg/ml) and IL-4+TGF-β (16 pg/ml). CCL-24 was not secreted by HRPE under all of the conditions tested. CCL-26 secretion found in HRPE treated with IL-4 (19 pg/ml) was increased in the presence of IL-4+TNF-α (30 pg/ml) and IL-4+IL-1β (28 pg/ml). Treatment of HRPE with other interleukins (IL-2, -5, -6, -8, -10, -11, -12, -13 or -18) + IL-4 had no effect on CCL-11 and CCL-26 secretion.
Inflammatory cytokines (IC) are potent inducers of secretion of CCL-5 and CCL-7 by HRPE. Secretion of CCL-5 and CCL-7 100-fold over CCL-11 and CCL-26 by HRPE suggests that CCL-5 and CCL-7 may play prominent roles as CCR-3 ligands in CNV in AMD. Pathological states leading to chronic inflammation may result in release of CCR-3 ligands that promote neovascularization processes in AMD.
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