INFLAMMATORY CYTOKINES INDUCE INTERCELLULAR-ADHESION MOLECULE-1 (ICAM-1) MESSENGER-RNA SYNTHESIS AND PROTEIN SECRETION BY HUMAN RETINAL-PIGMENT EPITHELIAL-CELL CULTURES

Retinal inflammatory diseases in man are associated with an upregulati on in the expression of intercellular adhesion molecule-1 (ICAM-1) in cells within the retina and with an increase in soluble ICAM-1 within the vitreous, These studies suggest that this protein may contribute t o immunopathological processes within the eye, The effects of inflamma tory mediators on the regulation of the expression and secretion of IC AM-1 by human retinal pigment epithelial cell cultures (HRPE) were inv estigated in order to identity the possible source of soluble ICAM-1 a nd the conditions which enhance its production, Immunofluorescence stu dies on TNF-alpha and/or IFN-gamma treated HRPE cells demonstrated cel lular expression of ICAM-1 which was predominantly localized to interc ellular junctions, Moreover, treatment of HRPE for 24 h with tumour ne crosis factor alpha (TNF-alpha) (10 ng/ml), interferon gamma (IFN-gamm a) (500 u/ml), interleukin 1 alpha (IL-1 alpha) (10 ng/ml) and IL-1 be ta (10 ng/ml) results in the secretion of ICAM-1, ranging from 9 to 13 ng per 10(6) cells, IFN-gamma acts synergistically with (TNF-alpha) a nd IL-1 in the secretion of ICAM-1 by HRPE. Only 1.75 ng of soluble IC AM-1 was detected in untreated HRPE cells, In contrast, lipopolysaccha ride (LPS), IL-6, IFN-alpha or TGF-beta did not exhibit any influence on ICAM-1 secretion by these cells, Northern blot analysis reveals an increased expression of ICAM-1 mRNA in HRPE stimulated with IFN-gamma, TNF-alpha or IL-1 for 24 h, In untreated cells, ICAM-1 mRNA is not de tectable, There is a progressive increase in ICAM-1 mRNA levels in cyt okine-treated HRPE, that reaches steady state by 12 h, Furthermore, a close correlation is noted between ICAM-1 mRNA levels and the secretio n of ICAM-1 protein, suggesting regulation at the level of gene transc ription, ICAM-1 secretion by RPE might actively participate in the imm une reactions in the retina, by recruiting and activating lymphocytes, and contribute to the immunopathological processes in inflammatory di seases. (C) 1996 Academic Press Limited