Retinal Pigment Epithelium-immune System Interactions: Cytokine Production and Cytokine-induced Changes
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).
Section snippets
Interleukin 1 and its antagonist
Interleukin (IL) 1 was originally identified as a monocyte product capable of stimulating T-cell proliferation. It is now clear that IL-1 is one of the most potent multifunctional cell activators stimulating immune cells and other cell types and that it serves as a ‘proximal’ mediator in many immune responses (Di Giovine and Duff, 1990). Most of these effects lead to activation of the immune system or stimulation of inflammatory responses and thus IL-1 is regarded a pro-inflammatory cytokine.
Cytokine receptor expression and signal transduction in rpe cells
Cytokines exert their effects on cells only after binding to specific receptors on the cell surface. The fact that RPE cells produce a variety of important immunological mediators in response to various cytokines (Table 2; Fig. 3) implies that these cells have surface expression of a number of cytokine receptors. Few studies, however, have actually demonstrated the presence of cytokine receptors on RPE cells. Besides the expression of the receptors for bFGF, PDGF and IGF (described above),
Cytokine production
Cytokine production by RPE cells in response to cytokines has been discussed extensively above. It is noteworthy that RPE cells express both the receptor and the ligand in case of IL-1, IL-6, IL-15, TNF, TGF, FGF, IGF, VEGF and PDGF, suggesting that autocrine or paracrine effects may be induced by these cytokines. In situ hybridization may reveal whether there are subpopulations of RPE cells producing only the cytokine and only the receptor or whether the cytokine and its receptor are expressed
Conclusions and future directions
The studies described here reveal that RPE cells act as a source of cytokines in the posterior part of the eye and form a target for inflammatory cytokines. It has been suggested that cytokines produced by RPE cells may play an important role in the homeostasis of the retina, as well as in inflammatory responses by activation of resident cells and attraction and activation of inflammatory cells.
The current knowledge of the effects of cytokines on RPE cells and cytokine production by RPE cells,
Acknowledgements
The authors thank Nico Bakker and Tom Put for their help in preparing the illustrations.
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