Regulation of granulocyte-macrophage colony-stimulating factor in human retinal pigment epithelial cells by IL-1beta and IFN-gamma

GM-CSF production by RPE cells, which form part of the blood-retina barrier, is upregulated by IL-1 beta and this increase can be reversed by LFN-beta. IL-1 beta up-regulation is not dependent on PKC but the PKC activator PMA induces low levels of GM-CSF production and acts synergistically with IL-1 beta to further increase GMCSF. Although A23187 and ionomycin stimulated low levels of GM-CSF production, the IL-1 beta pathway was cyclosporin A insensitive and did not interact with the calcium pathway. TL-1 beta -stimulated GM-CSF mRNA expression and production was strongly dependent on MF-kappaB. IFN-gamma inhibition of the GM-CSF response to IL-1 beta acted via NF-kappaB, reducing the translocation of NF-kappaB to the nuclei of RPE cells treated with IL-1 beta and IFN-gamma. The results show that IFN-gamma down-regulation acts either directly on NF-kappaB or its activation or by blockade of a pathway upstream of NF-kappaB. However, any such blockade does not involve PKC or intracellular calcium. (C) 2001 Academic Press.