Regulation Of Cytokine Signaling Pathways In The Eye

Egwuagu, Charles

Abstract

Cytokines and growth factors play important roles in regulating the growth and development of the eye and a number of ocular diseases result from aberrant activation of these factors. One of the goals of this project is to investigate whether growth factors implicated in lens growth, differentiation and development mediate their effects through activation of JAK/STAT signal transduction pathways and if growth-factor-induced STAT-signaling in the lens is under feedback regulation by suppressors of cytokine signaling (SOCS). Our results indicate that STAT proteins are constitutively expressed at low levels and activated by insulin-like growth factor (IGF-1), platelet-derived growth factor (PDGF), fibroblast growth factor 1 (FGF-1) or FGF-2 in the lens. Intensity of STAT signaling increases at high FGF-2 concentration and FGFs synergize with IGF-1 or PDGF to enhance STAT-signaling and SOCS expression. We also found that growth factor-induced proliferation of lens cells is inhibited by AG-490, a specific inhibitor of JAK2/STAT3. This is the first report that FGFs activate STAT pathways in the lens and that SOCS proteins are constitutively expressed and up-regulated by growth factors in this tissue. Physiological relevance of STAT pathways in the lens is underscored by inhibition of lens proliferation by inhibitors of JAK/STAT pathways and by the aberrant proliferation of lens epithelia in posterior pole of transgenic mice with constitutively activated STAT1 in the lens. Common activation of STAT pathways by FGF-1, FGF-2, IGF-1 or PDGFaa and their synergistic activation of STATs and SOCS in lens cells, suggest that activities and crosstalk between these factors are sensitive to the steady-state levels of activated STATs in the lens and may be under feedback regulation by SOCS family proteins