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R. Mahdi, C.-R. Yu, Y. Lee, X. Liu, A. Zhang, A. Amadi-Obi, C.-C. Chan, I. Gery, C. Egwuagu; Socs1 Regulates Development of Intraocular Inflammation. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5198.
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Cytokines regulate immune homeostasis and stringent control over cytokine activities ensures adequate immunological responses while preventing development of autoimmune diseases. Suppressors of cytokine signaling (SOCS) proteins regulate cytokine activities, T-cell activation and migration and influence cell-fate decisions of naive T-cells. In this study we have generated SOCS1-deficient mice and transgenic rats with targeted expression of SOCS1 (SOCS-TR) in retina and used them to examine roles of SOCS1 in intraocular inflammation.
SOCS1-/-/STAT1 mice were generated by mating SOCS+/- and STAT1-/- mice and their phenotype was characterized by ELISA, Western blotting, qRT-PCR and histology. An opsin-specific promoter element was used to generate the SOCS-TR rats. Experimental autoimmune uveoretinitis (EAU) was induced by immunization with S-Antigen.
Our data reveal the following: (i) SOCS1-deficient mice have severe chronic inflammatory eye disease characterized by orbital cellulites/abscess, corneal ulcers and neovascularization, iritis, vitritis, retinitis, retinal edema, retinitis and hemorrhage; (ii) ability of inflammatory cells to infiltrate various ocular tissues of the eye correlates with upregulation of the Th1-specific chemokine receptor, CXCR3, and down-regulation of CCR7, a chemokine receptor associated with restricting inflammatory cells to secondary lymphoid organs; (iii) Elevated levels of IL-17 and IFNγ are detected in eyes of the DKO mice and peripheral lymphocytes express copious amounts of IL-6, IL-17 and IFNγ; (iv) In S-Ag immunized rats, 3 of 7 SOCS1-TR rats did not develop EAU while all 7 wild type rats developed severe EAU.
The development of chronic inflammatory disease in SOCS1-deficient mice and the partial protection of SOCS1 transgenic rats from development of EAU underscore the critical role of SOCS1 in mitigating the development of chronic intraocular inflammation. It is therefore possible that SOCS proteins, particularly SOCS1, might prove to be relevant therapeutic targets for treatment of chronic ocular inflammatory and autoimmune diseases.
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