Abstract
Chemokine reeptor-3 (CCR-3) was shown to be associated with choroidal neovascularization (CNV) in age-related macular degeneration (AMD). AMD is a vision threatening retinal disease that affects the aging population world-wide. Retinal pigment epithelium and choroid in the posterior part of the retina are the key tissues targeted in the pathogenesis of CNV in AMD. We used human retinal pigment epithelial (HRPE) and choroidal fibroblast (HCHF) cells, prepared from aged adult human donor eyes, to evaluate the expression of major CCR-3 ligands, CCL-5, CCL -7, CCL-11,CCL-24 and CCL-26. Microarray analysis of gene expression in HRPE cells treated with inflammatory cytokine mix (ICM= IFN-γ+TNF-α+IL-1β) revealed 75 and 23-fold increase in CCL-5 and CCL-7 respectively, but not CCL-11, CCL-24 and CCL-26. Chemokine secretion studies of the production of CCL5 and CCL7 by HRPE corroborated with the gene expression analysis data. When the HRPE cells were treated with either individual cytokines or the ICM, both CCL-5 and CCL-7 were produced in a dose dependent manner. Similar to the gene expression data, the ICM did not enhance HRPE production of CCL-11, CCL-24 and CCL-26. CCL-11 and CCL-26 were increased with IL-4 treatment and this HRPE production was augmented in the presence of TNF-α and IL1β. When HCHF cells were treated with either individual cytokines or the ICM, both CCL-5 and CCL-7 were produced in a dose dependent fashion. IL-4 induced low levels of CCL-11 and CCL-26 in HCHF and this production was significantly enhanced by TNF-α. Under these conditions, neither HRPE nor HCHF were demonstrated to produce CCL-24. These data demonstrate that chronic inflammation triggers CCL-5 and CCL-7 release by HRPE and HCHF and the subsequent interactions with CCR3 may participate in pathologic processes in AMD.
Highlights
Chemokine reeptor-3 (CCR-3) was shown to be associated with choroidal neovascularization (CNV) in age-related macular degeneration (AMD)
Since the individual inflammatory cytokines or inflammatory cytokine mix (ICM) did not induce the production of eotaxins (CCL-11, -24 and 26) by human retinal pigment epithelial (HRPE) and HCHF cells, we examined the effects of a number of other cytokines and growth factors
Microarray analysis of gene expression by HRPE treated with inflammatory cytokines We used the Affymetrix GeneChip human genome U133 plus 2.0 to evaluate the global gene expression profiles in HRPE cells that were treated with inflammatory cytokine mix (ICM) containing IFN, TNF- and IL-1
Summary
Chemokine reeptor-3 (CCR-3) was shown to be associated with choroidal neovascularization (CNV) in age-related macular degeneration (AMD). IL-4 induced low levels of CCL-11 and CCL-26 in HCHF and this production was significantly enhanced by TNF- Under these conditions, neither HRPE nor HCHF were demonstrated to produce CCL-24. We reported that inflammatory cytokines, IFN- , TNF- and IL-1 enhance the secretion of vascular endothelial growth factors (VEGF-A and VEGF-C) by human RPE and choroidal fibroblast cells [21, 27, 28]. These results suggest a direct link among inflammation, VEGF secretion and neovascularization
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