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Aging and disease    2015, Vol. 6 Issue (6) : 444-455     DOI: 10.14336/AD.2015.0323
Original Article |
Inflammatory Cytokines Induce Expression of Chemokines by Human Retinal Cells: Role in Chemokine Receptor Mediated Age-related Macular Degeneration
N. Nagineni Chandrasekharam1,*, K. Kommineni Vijay1, Ganjbaksh Nader1, K. Nagineni Krishnasai2(), J. Hooks John1, Detrick Barbara3,*()
1 Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA
2 School of Public Policy, University of Maryland, College Park, MD 20742, USA
3 Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA
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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.

Keywords Age-related macular degeneration      Retinal pigment epithelium      Retina      Inflammation      Choroidal neovascularization      Chemokines      CCR3     
Corresponding Authors: N. Nagineni Chandrasekharam,Detrick Barbara     E-mail: naginenic@mail.nih.gov;bdetrick@jhmi.edu
About author:

present address: Kunming Biomed International, Kunming, Yunnan, 650500, China

Issue Date: 01 December 2015
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N. Nagineni Chandrasekharam
K. Kommineni Vijay
Ganjbaksh Nader
K. Nagineni Krishnasai
J. Hooks John
Detrick Barbara
Cite this article:   
N. Nagineni Chandrasekharam,K. Kommineni Vijay,Ganjbaksh Nader, et al. Inflammatory Cytokines Induce Expression of Chemokines by Human Retinal Cells: Role in Chemokine Receptor Mediated Age-related Macular Degeneration[J]. Aging and disease, 2015, 6(6): 444-455.
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2015.0323     OR     http://www.aginganddisease.org/EN/Y2015/V6/I6/444
Gene nameFold increase
CXCL-2 [GROβ) Fold increase185
CXCL-3 [GROγ] Fold increase102
CXCL-5 [ENA-78] Fold increase23
CXCL-6 [GCP-2]67
CXCL-8 [IL-8]112
CXCL-9 [MIG]48
CXCL-10 [IP-10]176
CXCL-11 [I-TAC]175, 148
CXCL-12 [SDF-1]ND
CXCL-14 [BRAK]2
CX3CL-1 [Fractalkine]110, 31
CCL-2 [MCP-1]55
CCL-3 [MIP-1α]3
CCL-4 [MIP-1β]2
CCl-5 [RANTES]75, 56
CCL-7 [MCP-3]23
CCL-8 [MCP-2]ND
CCL-11 [Eotaxin-1]ND
CCL-13 [MCP-4]ND
CCL-15 [MIP-1δ]ND
CCL-20 [MIP-3α]62
CCL-24 [Eotaxin-2]ND
CCL-26 [Eotaxin-3]ND
Table 1  Expression of chemokine genes by human retinal pigment epithelial cells (HRPE).
Figure 1.  Effect of inflammatory cytokines on CCL-5 (RANTES) and CCL-7 (MCP-3) secretion by human retinal pigment epithelial (HRPE) cells. (A and B) HRPE cells grown to confluence in 24 well (1 ml/well) plates were treated with IFN-γ (100 u/ml), TNF-α (10 ng/ml) or IL-1β (10 ng/ml) and various combinations of these cytokines for 24h in serum free medium (SFM). (C and D) HRPE cells were treated with various concentrations of inflammatory cytokine mix (ICM, 10x to 0.01x) for 24h in SFM. ICM 10x is IFN-γ (100 u/ml), TNF-α (10 ng/ml) or IL-1β (10 ng/ml). Levels of CCL-5 and CCL-7 in the culture supernatants were determined by ELISA as described in the methods section. Results are means ± of 4-5 independent experiments each with duplicate samples. * p values < 0.001 compared to IFN-γ alone.
Figure 2.  Effect of interleukin-4 (IL-4) and inflammatory cytokines on CCL-11 (eotaxin-1) and CCL-26 (eotaxin-3) secretion by HRPE cells. HRPE cells grown to confluence in 24 well (1 ml/well) plates were treated with IL-4 (10 ng/ml), TNF-α (10 ng/ml), IFN-γ (100 U/ml), IL-1β (10 ng/ml) or various combinations of these cytokines for 24h in SFM. Levels of CCL-11 (A) and CCL-26 (B) in culture supernatants were determined by ELISA. Results are means ± of 4 independent experiments each with duplicate samples. * P values <0.001 compared to IL-4 alone.
Figure 3.  Effect of IL-4 and inflammatory cytokines on CCL-5 and CCL-7 secretion by HRPE cells. HRPE cells grown to confluence in 24 well (1 ml/well) plates were treated with IL-4 (10 ng/ml), TNF-α (10 ng/ml), IFN-γ (100 U/ml), IL-1β (10 ng/ml) or various combinations of these cytokines for 24h in SFM. Levels of CCL-5 (A) and CCL-7 (B) in culture supernatants were determined by ELISA. Results are means ± of 4 independent experiments each with duplicate samples. * P values <0.001 compared to TNF-α alone.
Figure 4.  Effect of inflammatory cytokines on CCL-5 (RANTES) and CCL-7 (MCP-3) secretion by human choroidal fibroblast (HCHF) cells. (A and B) HCHF cells grown to confluence in 24 well (1 ml/well) plates were treated with IFN-γ (100 u/ml), TNF-α (10 ng/ml) or IL-1β (10 ng/ml) and various combinations of these cytokines for 24h in serum free medium (SFM). (C and D) HCHF cells were treated with various concentrations of inflammatory cytokine mix (ICM, 10x to 0.01x) for 24h in SFM. ICM 10x is IFN-γ (100 u/ml), TNF-α (10 ng/ml) or IL-1β (10 ng/ml). Levels of CCL-5 and CCL-7 in the culture supernatants were determined by ELISA as described in the methods section. Results are means ± of 4-5 independent experiments each with duplicate samples.
Figure 5.  Effect of IL-4 and inflammatory cytokines on CCL-11 (eotaxin-1) and CCL-26 (eotaxin-3) secretion by HCHF cells. HCHF cells grown to confluence in 24 well (1 ml/well) plates were treated with IL-4 (10 ng/ml), TNF-α (10 ng/ml), IFN-γ (100 U/ml), IL-1β (10 ng/ml) or various combinations of these cytokines for 24h in SFM. Levels of CCL-11 (A) and CCL-26 (B) in culture supernatants were determined by ELISA. Results are means ± of 4 independent experiments each with duplicate samples. * P values <0.001 compared to IL-4 alone.
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