One of our objectives in this study was to investigate whether the aberrant upregulation of cytokine secretion in patients with persistent ocular inflammatory disease derives in part from defects in proteins that mediate negative feedback regulation of activities of proinflammatory cytokine. We found that PBMC of patients with scleritis could not induce the expression of the negative feedback regulatory protein SOCS1. Because ethical considerations and NIH IRB guidelines precluded obtaining retinal tissue biopsy to determine whether SOCS expression is also defective in ocular tissues of scleritis patients, we generated transgenic mice and rats with over-expression of SOCS1 in the retina and used these animals to further investigate the role of SOCS1 in the retina and intraocular inflammatory diseases. Although results from several studies suggest that induction of SOCS1, SOCS3 and CIS by inflammatory cells mitigates immune responses by regulating the intensity and duration of cytokine signals, until now it has not been clear whether retinal cells also produce SOCS1 and what physiological role they might have during ocular inflammation. By targeting the over-expression of SOCS1 to the retina of rats and mice and examining the in vivo function of SOCS1 in the well-characterized EAU model, we show that SOCS1 protects mice and rats from developing severe uveitis. Our data suggests that proinflammatory cytokines produced during EAU induces retinal cells to repress the production of chemotactic cytokines and this results in substantial decrease in the numbers of pathogenic T cells recruited into the retina during uveitis. Defective expression of SOCS1 in patients with scleritis, taken together with our data showing that SOCS1 mediated protection of neuroretinal cells from apoptosis, suggests that SOCS1 has neuroprotective function in the retina and imply that administration of SOCS1 mimetic peptides maybe useful in treating uveitis or scleritis.

National Institute of Health (NIH)
National Eye Institute (NEI)
Investigator-Initiated Intramural Research Projects (ZIA)
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U.S. National Eye Institute
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