May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Defective Production of IL-27 and Enhanced IL-23 Secretion by Dendritic Cells Contribute to Severe Experimental Autoimmune Uveitis of STAT1 Knockout Mice
Author Affiliations & Notes
  • Y. Lee
    Molecular Immunology, NEI/NIH, Bethesda, Maryland
  • C.-R. Yu
    Molecular Immunology, NEI/NIH, Bethesda, Maryland
  • X. Liu
    Molecular Immunology, NEI/NIH, Bethesda, Maryland
  • C. E. Egwuagu
    Molecular Immunology, NEI/NIH, Bethesda, Maryland
  • Footnotes
    Commercial Relationships  Y. Lee, None; C. Yu, None; X. Liu, None; C.E. Egwuagu, None.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 4765. doi:
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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.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : 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.

Methods: : 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.

Results: : 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.

Conclusions: : 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.

Keywords: inflammation • signal transduction • uveitis-clinical/animal model 
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