PDGF-C and -D Induced Proliferation/Migration of Human RPE Is Abolished by Inflammatory Cytokines

Li, Rong; Maminishkis, Arvydas; Wang, Fei E.; Miller, Sheldon S.

doi:10.1167/iovs.07-0327

Cited by 53 publications

(42 citation statements)

References 57 publications

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“…More recently, IFN-λ has been discovered and it is currently the sole member of the type 3 subclass [27]. Type 1 interferon including IFN-α and β have antiproliferative and anti-angiogenic effects and has an antagonistic role to IFN-γ [28][29][30][31][32]. In the 1990s, IFN-α and β were used in the treatment of AMD [33][34][35].…”

Section: Is Ifn-γ a Possible Target For Treatment Of Amd?mentioning

confidence: 99%

Immuno-modulatory Effect of IFN-gamma in AMD and its Role as a Possible Target for Therapy

Jiang¹,

Cao²

2012

J Clin Exp Ophthalmol

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Age-related macular degeneration (AMD) is a neurodegenerative disease characterized by retinal cell atrophy, and/or choroidal neovascularization in the macula and constitutes the most common cause of blindness among the elderly in industrialized countries. The management of AMD is constrained by our insufficient knowledge of its underlying mechanisms. Recent studies point towards an emerging involvement of interferon-gamma (IFN-γ), a soluble cytokine associated with innate and adaptive immunity. IFN-γ promotes proinflammatory responses by activating proinflammatory cytokines and chemokines, thereby recruiting immune cells such as macrophages and T cells. On the other hand, IFN-γ modulates inflammatory response by upregulating antiinflammatory factors or inhibiting development of immune cells related to autoimmune response. The complex role of IFN-γ in AMD pathogenesis is intriguing and worth further investigation in terms of therapeutic development.

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Section: Is Ifn-γ a Possible Target For Treatment Of Amd?mentioning

confidence: 99%

Immuno-modulatory Effect of IFN-gamma in AMD and its Role as a Possible Target for Therapy

Jiang¹,

Cao²

2012

J Clin Exp Ophthalmol

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“…In previous experiments we have used these primary cultures to determine the expression, polarization and function of plasma membrane transport proteins and identify specific signaling pathways that regulate RPE function [1][2][3][4][5][6][7][8][9][10][11] These characteristics as they are accumulated provide a validation set of properties that can be applied to each cell generation. The experiments summarized below identify the proteins that determine transepithelial fluid transport and the integrity of the paracellular pathway.…”

Section: Functional Validation Of Hfrpe Cell Culturementioning

confidence: 99%

Experimental Models for Study of Retinal Pigment Epithelial Physiology and Pathophysiology

Maminishkis

Miller

2010

JoVE

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We have developed a cell culture procedure that can produce large quantities of confluent monolayers of primary human fetal retinal pigment epithelium (hfRPE) cultures with morphological, physiological and genetic characteristics of native human RPE. These hfRPE cell cultures exhibit heavy pigmentation, and electron microscopy show extensive apical membrane microvilli. The junctional complexes were identified with immunofluorescence labeling of various tight junction proteins. Epithelial polarity and function of these easily reproducible primary cultures closely resemble previously studied mammalian models of native RPE, including human. These results were extended by the development of therapeutic interventions in several animal models of human eye disease. We have focused on strategies for the removal of abnormal fluid accumulation in the retina or subretinal space. The extracellular subretinal space separates the photoreceptor outer segments and the apical membrane of the RPE and is critical for maintenance of retinal attachments and a whole host of RPE/retina interactions.

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“…It is recently shown that PDGF-CC induces blood-brain barrier permeability during ischemic stroke (11,12). PDGF-CC is abundantly expressed in the eye (13) and induces proliferation and migration of retinal pigment epithelial (RPE) cells (14). Furthermore, PDGF-CC plays important roles in recruiting fibroblasts associated with drug resistance in tumors (15)(16)(17).…”

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confidence: 99%

PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets

Kumar

Lee

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The importance of identifying VEGF-independent pathways in pathological angiogenesis is increasingly recognized as a result of the emerging drug resistance to anti-VEGF therapies. PDGF-CC is the third member of the PDGF family discovered after more than two decades of studies on PDGF-AA and PDGF-BB. The biological function of PDGF-CC and the underlying cellular and molecular mechanisms remain largely unexplored. Here, using different animal models, we report that PDGF-CC inhibition by neutralizing antibody, shRNA, or genetic deletion suppressed both choroidal and retinal neovascularization. Importantly, we revealed that PDGF-CC targeting acted not only on multiple cell types important for pathological angiogenesis, such as vascular mural and endothelial cells, macrophages, choroidal fibroblasts and retinal pigment epithelial cells, but also on the expression of other important angiogenic genes, such as PDGF-BB and PDGF receptors. At a molecular level, we found that PDGF-CC regulated glycogen synthase kinase (GSK)–3β phosphorylation and expression both in vitro and in vivo. Activation of GSK3β impaired PDGF-CC–induced angiogenesis, and inhibition of GSK3β abolished the antiangiogenic effect of PDGF-CC blockade. Thus, we identified PDGF-CC as an important candidate target gene for antiangiogenic therapy, and PDGF-CC inhibition may be of therapeutic value in treating neovascular diseases.

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PDGF-C and -D Induced Proliferation/Migration of Human RPE Is Abolished by Inflammatory Cytokines

Cited by 53 publications

References 57 publications

Immuno-modulatory Effect of IFN-gamma in AMD and its Role as a Possible Target for Therapy

Immuno-modulatory Effect of IFN-gamma in AMD and its Role as a Possible Target for Therapy

Experimental Models for Study of Retinal Pigment Epithelial Physiology and Pathophysiology

PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets

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