Indoleamine 23-dioxygenase overexpression causes kynurenine-modification of proteins fiber cell apoptosis and cataract formation in the mouse lens

摘要

Indoleamine 2,3-dioxygenase (IDO) is the first enzyme in the kynurenine pathway. The kynurenines formed in this pathway chemically modify proteins and cause apoptosis in cells. Evidence suggests that kynurenines and their protein modifications are involved in cataract formation, but this has yet to be directly demonstrated. We generated transgenic mouse lines (Tg) that overexpress human IDO in the lens. Homozygous Tg (homTg) lenses had higher IDO immunoreactivity, ~4.5 times greater IDO mRNA, and ~8 times higher IDO activity compared to lenses from hemizygous Tg animals (hemTg). The kynurenine content was 3-fold higher in homTg than hemTg but was not detected in Wt lenses. Kynurenine-modifications were ~2.6 times greater in homTg than hemTg or Wt. HomTg lenses had vacuoles in the epithelium and cortical fiber cells. Kynurenine-modifications coincided with apoptosis in the secondary fiber cells of homTg lenses. Caspase-3 and -9 activities were markedly higher in homTg than in hemTg and Wt. The GSH content was ~36% lower in homTg compared to hemTg and Wt lenses. HomTg animals also developed bilateral cataracts within 3 months of birth. Together these data demonstrate that IDO-mediated production of kynurenines results in defects in fiber cell differentiation and their apoptosis and suggest that IDO activity is kept low in the lens to prevent deleterious effects by kynurenines.