Inflammatory cytokines regulate microRNA-155 expression in human retinal pigment epithelial cells by activating JAK/STAT pathway.
Inflammatory response of the retinal pigment epithelium plays a critical role in the pathogenesis of retinal degenerative diseases such as age-related macular degeneration. Our previous studies have shown that human retinal pigment epithelial (HRPE) cells, established from adult donor eyes, respond to inflammatory cytokines by enhancing the expression of a number of cytokines and chemokines. To investigate the role of microRNA (miRNA) in regulating this response, we performed microarray analysis of miRNA expression in HRPE cells exposed to inflammatory cytokine mix (IFN-γ+TNF-α+IL-1β). Microarray analysis revealed ∼11-fold increase in miR-155 expression, which was validated by real-time PCR analysis. The miR-155 expression was enhanced when the cells were treated individually with IFN-γ, TNF-α or IL-1β, but combinations of the cytokines exaggerated the effect. The increase in miR-155 expression by the inflammatory cytokines was associated with an increase in STAT1 activation as well as an increase in protein binding to putative STAT1 binding elements present in the MIR155 gene promoter region. All these activities were effectively blocked by JAK inhibitor 1. Our results show that the inflammatory cytokines increase miR-155 expression in human retinal pigment epithelial cells by activating the JAK/STAT signaling pathway.
Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. kuttyk@nei.nih.gov
R Krishnan
RK
Kutty
Chandrasekharam N
CN
Nagineni
William
W
Samuel
Camasamudram
C
Vijayasarathy
John J
JJ
Hooks
T Michael
TM
Redmond
D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D053612:Janus Kinases / Q000096:biosynthesis*; D035683:MicroRNAs / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*
D016207:Cytokines; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D053612:Janus Kinases