title: IFN-beta provides immuno-protection in the retina by inhibiting ICAM-1 and CXCL9 in retinal pigment epithelial cells.
abstract: The retinal pigment epithelial (RPE) cell is a potent regulatory cell that facilitates normal physiologic processes and plays a critical role in a variety of retinal diseases. We evaluated IFN-beta production in human RPE cells through TLR signaling and investigated the effects of IFN-beta on RPE cells. RPE cells treated with poly(I:C) or infected with an RNA virus produce IFN-beta. Kinetic studies revealed that IFN-beta levels continue to increase over a 48-h period and this was associated with the up-regulation of IRF-7 gene expression, a known positive feedback molecule for IFN-beta production. Microarray analysis revealed that in IFN-beta treated cells, 480 genes of 22,283 genes were up or down-regulated by >2-fold. We hypothesize that IFN-beta induction during TLR signaling in the retina is an immunosuppressive factor produced to limit immunopathologic damage. Cytokine activation of RPE cells results in the production of the chemokines, CXCL9 and CXCL10, and the adhesion molecule, ICAM-1. Pretreatment of RPE cells with IFN-beta resulted in inhibition of ICAM-1 production and elimination of CXCL9 production. This treatment did not alter CXCL10 production. Anti-IFN-beta Ab blocked the inhibitory action of IFN-beta. Real time PCR analysis revealed that IFN-beta treatment inhibited gene expression of sICAM-1 and CXCL9. The results indicate a critical role for RPE cell derived IFN-beta in the down-regulation of CXCL9 and ICAM-1 expression in the retina and suggest that the inhibition of CXCL9 is an immuno-suppressive mechanism that protects the retina from excessive inflammation.
authors.affiliation: Immunology and Virology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. hooksj@nei.nih.gov
authors.forename: John J
authors.initials: JJ
authors.lastname: Hooks
authors.forename: Chandrasekharam N
authors.initials: CN
authors.lastname: Nagineni
authors.forename: Laura C
authors.initials: LC
authors.lastname: Hooper
authors.forename: Kozaburo
authors.initials: K
authors.lastname: Hayashi
authors.forename: Barbara
authors.initials: B
authors.lastname: Detrick
mesh_terms: D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D054370:Chemokine CXCL9 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000378:metabolism*; D016899:Interferon-beta / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D007700:Kinetics; D020411:Oligonucleotide Array Sequence Analysis; D010857:Pigment Epithelium of Eye / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D012173:Retinitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology
chemical_list: C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018836:Inflammation Mediators; D018799:Intercellular Adhesion Molecule-1; D016899:Interferon-beta