Suppressor of cytokine signaling (SOCS) are an 8-member family of intracellular proteins that function as components of a negative feedback loop that regulate the initiation, intensity, duration, and quality of cytokine responses. SOCS proteins are rapidly induced in many cell types in response to cytokines (IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-12, IL-21, IL-23, IL-27) or growth factors (CNTF, LIF, FGF, IGF-1, insulin) and their inhibitory effects derive from direct interaction with cytokine/growth-factor receptors or signaling proteins, leading to proteosomal degradation of the receptor complex and termination of the signal. Because of the relatively short half-life of SOCS proteins, their negative regulatory effects are generally transient. However, unabated stimulation of STAT signaling pathway by chronic inflammation or cellular stress can induce constitutive activation of SOCS expression. In some tissues this may result in persistent silencing of critical cellular pathways and pre-disposition to development of organ-specific disease. In this study, we found that lymphocytes of patients with scleritis are defective in SOCS1 expression. To further investigate potential role of SOCS1 in ocular inflammatory diseases we generated transgenic rats and mice with over-expression (SOCS1-Tg) or deletion (SOCS1KO) of SOCS1 in retina. We show that expression of some chemokines and chemokine recptors is regulated by SOCS1 and that over-expression of SOCS1 in retina substantially reduced recruitment of inflammatory cells into retina and protected SOCS1-Tg from developing severe uveitis. Defective expression of SOCS1 in patients with scleritis, taken together with our data showing that SOCS1 protects neuroretinal cells from apoptosis, suggest that SOCS1 has a neuroprotective function in the retina and imply that administration of SOCS1 mimetic may be useful in treating uveitis or scleritis.
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