Cytokine regulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) production by human retinal pigment epithelial cells

GM-CSF is an important regulator of macrophage, granulocyte and dendritic c ell behaviour and function. These cell types have been implicated in the re tinal damage characteristic of endogenous posterior uveitis. Dendritic cell s in the choroid have access to retinal antigens processed by the retinal p igment epithelial (RPE) cells of the blood-retinal barrier and are thought to be candidates for the presentation of antigen in uveoretinitis. We there fore investigated the production of GM-CSF and its regulation in human RPE cells. IL-1 beta, tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) all stimulated GM-CSF production by RPE cell s and a combination of these cytokines increased GM-CSF production over fiv e-fold compared with that with the individual cytokines alone. Interferon-g amma (IFN-gamma) rapidly down-regulated these responses. IFN-gamma did not appear to be acting directly on IL-1 beta or via the synthesis of another p rotein. GM-CSF mRNA expression showed the same pattern of response to these cytokines, indicating transcriptional or pre-transcriptional regulation, a nd there was no evidence that IFN-gamma was acting by destabilizing GM-CSF mRNA. These results are generally important in understanding the ways in wh ich cytokine regulation differs between different cell types and also more specifically for determining ways in which a cytokine with a significant ro le in the development of autoimmune uveoretinitis may be manipulated.