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Y. Lee, C.-R. Yu, X. Liu, C. E. Egwuagu; Defective Production of IL-27 and Enhanced IL-23 Secretion by Dendritic Cells Contribute to Severe Experimental Autoimmune Uveitis of STAT1 Knockout Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4765. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Dendritic cells (DC) secreting IL-27 and IL-23 regulate development TH17 cells and this T-cell subtype has recently been implicated in the etiology of human uveitis and mouse experimental autoimmune uveitis (EAU). IL-27 preferentially activates STAT1, induces naive T- cells to differentiate into TH1 cells while antagonizing development into TH17 lineage. On the other hand, IL-23 preferential activates STAT3 pathways and promotes TH17 development. In this study, we have examined whether differential production of IL-27 and IL-23 by DC during priming of naive T- cells is regulated by STAT pathways. We have also used STAT-deficient mice to study the role of STAT pathways in EAU.
DCs were generated from bone marrow derived hematopoietic stem cells and phenotype of precursor (pDC) and immature (iDC) mature (mDC) was characterized by ELISA, intracellular cytokine staining, qRT-PCR and Flow cytometry. Regulation of IL27p28 gene was analyzed by CHIP assay. Effects of STAT-deficiency (STATKO) on in vivo differentiation to TH17 or EAU were studied in WT or STAT1KO mice immunization with IRBP in CFA.
STAT1KO DC is characterized by: (i) Elevated levels of IL-23; (ii) Reduced secretion of IL-27; (iii) Reduced expression of DC maturation markers at all DC developmental stages. We also show that STAT1 binds IL27p28 promoter, underscoring requirement of STAT1 for IL-27 expression. In co-culture experiments with naive T-cells, STAT1KO mDC induced the development of more TH17 cells compared to WT DC. In vivo studies reveal that enhanced TH17 production in STAT1KO mice correlates with the development of a more severe EAU.
The data presented reveal that STAT1 is required for DC maturation and secretion IL-27 and may contribute to the inhibition of IL-17-mediated organ-specific autoimmune diseases. Increased secretion of IL-23 by STAT1KO DC further suggests that STAT1 is a dominant-negative regulator of IL-23 production by DC. Thus, requirement of STAT1 for DC maturation may be exploited in development of DC vaccines.
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