Retinal Pigment Epithelium-immune System Interactions: Cytokine Production and Cytokine-induced Changes

Abstract

Vision is dependent on proper function of several intraocular structures. Immune responses to eliminate invading pathogens from the eye may threat vision by causing damage to these structures. Therefore, immunological defence of the eye should be carefully balanced between efficacy and maintenance of functional integrity. The eye is equipped with several regulatory mechanisms to prevent certain immune and inflammatory responses and is, therefore, regarded as an immune privileged site. The retinal pigment epithelium (RPE) contributes to the immune privileged status of the eye as part of the blood–eye barrier and by the secretion of immunosuppressive factors inside the eye. RPE cells, however, may also play an important role in the development of immune and inflammatory responses in the posterior part of the eye. During the last decade it has become clear that RPE cells are highly sensitive to a variety of inflammatory cytokines. Under inflammatory conditions, RPE cells produce a myriad of cytokines that may activate the resident ocular cells or attract and activate leukocytes. Cytokine stimulation of RPE cells causes profound effects, including nitric oxide secretion, cell surface expression of MHC class II and adhesion molecules and abrogation of barrier function. This article provides a comprehensive review of the literature concerning RPE cells and cytokines.

Introduction

The retinal pigment epithelium (RPE) is a monolayer of cells situated between the neuroretina and the choroid. The RPE is of neuro-ectodermal origin and is therefore considered to be part of the retina. RPE cells have important functions in maintaining homeostasis of the outer retina. These functions include regulating the transport of nutrients to the photoreceptors, phagocytosing old rod outer segments and absorbing stray light. Furthermore, the monolayer of RPE cells is part of the blood–eye barrier and limits access of blood components to the retina (Zinn and Benjamin-Henkind, 1979). Recently, it was found that FasL expression on RPE cells may play an important role in the control of subretinal neovascularisation (Kaplan et al., 1999). In addition, the RPE cells are thought to play an important role in immune responses and may help in maintaining immune privilege within the eye.

In vivo, the RPE cells display a polarised morphology with apical microvilli in between the rods and the cones and with infoldings at the basal side. RPE cells are connected to each other by tight junctions and as a result the RPE cell monolayer is impermeable for macromolecules. The tight junctions are situated at the apical side of the lateral membrane of the cells. Expression of some cell markers at the apical membrane, like ATPase, further demonstrates that the RPE cells are polarised (Gundersen et al., 1991). RPE cells can be cultured relatively easily and recently, it was found that RPE cells in vitro also display many in vivo characteristics including tight junction formation and a polarised morphology (Dunn et al., 1996; Tugizov et al., 1996; Holtkamp et al., 1998; Zech et al., 1998).

RPE cells have been implied to be involved in various pathological conditions. Age-related macular degeneration (AMD) is characterized by the accumulation of membranous debris on both sides of the RPE, whereby intracellular material accumulated inside the RPE cells causing dysfunction of the cells (Zarbin, 1998). Proliferative vitreoretinopathy (PVR) is a complication of retinal detachment. The hallmark of PVR is the formation of contractile epiretinal membranes (in which RPE cells are present). The contraction and the resulting distortion of the membranes appear to be dependent on RPE–matrix interactions (Hiscott et al., 1999). Retinitis pigmentosa (RP) is a heterogeneous group of inherited diseases that causes degeneration of the photoreceptor layer followed by alterations in the RPE (Milam et al., 1998). Furthermore, RPE cells are suggested to play a role in uveoretinitis by producing cytokines and by antigen presentation to T lymphocytes (De Vos et al., 1992; Forrester et al., 1995).

During the last decade it has become clear, mainly from in vitro studies, that RPE cells play an important role in immune responses by expression of major histocompatibility complex (MHC) molecules, adhesion molecules, FasL and cytokines. Cytokines secreted by RPE cells contribute in various manners to immune and inflammatory responses (Fig. 1), e.g. some RPE-derived cytokines prevent or downregulate immune responses (anti-inflammatory cytokines), while others initiate or augment immune responses (pro-inflammatory cytokines). This review will focus on the production of immunomodulatory cytokines by RPE cells (listed in Table 1) and on the immunological and inflammatory effects of cytokines on RPE cells (listed in Table 2).