Role Of Retinal Pigment Epithelium In Retinal Disorders

Nagineni, Chandrasek

Abstract

Retinal pigment epithelium (RPE), a single layer of cells present between the retina and choroid in the eye, is vital for the normal functioning of the retina. Many of the inflammatory, infectious and other diseases of the retina are associated with the degeneration and /or dysfunction of the RPE. We have developed human RPE cell culture system and have used this as a model to investigate the various roles of RPE in the pathophysiology of retinal disorders. We have focussed our attention on Transforming Growth factor-beta (TGF-b), since TGF-b is involved in retinal disorders of proliferative, inflammatory and infectious etiology. Retinal and Choroidal neovascularization (CNV), observed during age related macular degeneration (ARMD) and diabetic retinopathy, are the leading causes of visual impairment. Elevated expression of TGF-b in vitreous, retina and RPE has been closely correlated with the retinal fibrosis and CNV. Platelet derived growth factors (PDGF) are known to be associated with retinal proliferative and angiogenic disorders such as proliferative vitreoretinopathy (PVR) and age realted macular degeneration (ARMD). PDGF promotes proliferation and migration of fibroblasts, pericytes, smooth muscle, glial and RPE cells. Our studies indicated that TGF-b is a potent inducer of PDGF-AA and PDGF-AB in RPE cells while choroidal fibroblasts(CHF) do not produce PDGF. Receptors for PDGF are highly expressed on CHF but not on RPE. Human recombinant PDGF-isoforms (AA, AB, BB) significantly enhanced CHF proliferation, elongation and migration. In contrast no significant effects on RPE proliferation and migration were observed. These results show that PDGF secreted by RPE cells (stimulated by TGF-b) act on nearby connective tissue cells (fibroblasts) and possibly on vascular pericytes and smooth muscle cells. Consequent promotion of proliferation and migration of these target cells results in the pathogenesis of PVR and CNV in ARMD. Regulation of the expression of PDGF in RPE by TGF-b strongly suggests an important role for TGF-b in neovascularization associated with retinal disorders such as PVR and ARMD.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Eye Institute (NEI)
• Type: Intramural Research (Z01)
• Project #: 1Z01EY000277-12
• Application #: 6826681
• Study Section: (LI)
• Support Year: 12
• Fiscal Year: 2003

Institution

• Name: U.S. National Eye Institute
• Country: United States

Publications

Nagineni, Chandrasekharam N; William, Abitha; Cherukuri, Aswini et al. (2016) Inflammatory cytokines regulate secretion of VEGF and chemokines by human conjunctival fibroblasts: Role in dysfunctional tear syndrome. Cytokine 78:16-9

Nagineni, Chandrasekharam N; Cherukuri, Karthik S; Kutty, Veena et al. (2007) Interferon-gamma differentially regulates TGF-beta1 and TGF-beta2 expression in human retinal pigment epithelial cells through JAK-STAT pathway. J Cell Physiol 210:192-200

Hayashi, Kozaburo; Hooper, Laura C; Chin, Marian S et al. (2006) Herpes simplex virus 1 (HSV-1) DNA and immune complex (HSV-1-human IgG) elicit vigorous interleukin 6 release from infected corneal cells via Toll-like receptors. J Gen Virol 87:2161-9

Hooks, John J; Chin, Marian S; Srinivasan, Kumar et al. (2006) Human cytomegalovirus induced cyclooxygenase-2 in human retinal pigment epithelial cells augments viral replication through a prostaglandin pathway. Microbes Infect 8:2236-44

Djalilian, Ali R; Nagineni, Chandrasekharam N; Mahesh, Sankanaranayana P et al. (2006) Inhibition of inflammatory cytokine production in human corneal cells by dexamethasone, but not cyclosporin. Cornea 25:709-14

Nagineni, Chandrasekharam N; Kutty, Veena; Detrick, Barbara et al. (2005) Expression of PDGF and their receptors in human retinal pigment epithelial cells and fibroblasts: regulation by TGF-beta. J Cell Physiol 203:35-43

Chen, Kevin G; Szakacs, Gergely; Annereau, Jean-Philippe et al. (2005) Principal expression of two mRNA isoforms (ABCB 5alpha and ABCB 5beta ) of the ATP-binding cassette transporter gene ABCB 5 in melanoma cells and melanocytes. Pigment Cell Res 18:102-12

Kim, Ben J; Li, Zhuqing; Fariss, Robert N et al. (2004) Constitutive and cytokine-induced GITR ligand expression on human retinal pigment epithelium and photoreceptors. Invest Ophthalmol Vis Sci 45:3170-6

Kumar, Matam Vijay; Nagineni, Chandrasekharam N; Chin, Marian S et al. (2004) Innate immunity in the retina: Toll-like receptor (TLR) signaling in human retinal pigment epithelial cells. J Neuroimmunol 153:7-15

Nagineni, Chandrasekharam N; Samuel, William; Nagineni, Sahrudaya et al. (2003) Transforming growth factor-beta induces expression of vascular endothelial growth factor in human retinal pigment epithelial cells: involvement of mitogen-activated protein kinases. J Cell Physiol 197:453-62