Indoleamine 2,3-dioxygenase overexpression causes kynurenine-modification of proteins, fiber cell apoptosis and cataract formation in the mouse lens

Abstract

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.

Role of indoleamine 2,3-dioxygenase in health and disease

“…This inhibition of proliferation was reversed by 1-DL-MT treatment [581]. In contrast, when compared with lens epithelial cells, mouse lens fibre cells overexpressing human IDO1 are more susceptible, with IDO1-mediated fibre cell apoptosis evident even in pre-cataract lenses [591].…”

“…Protective [102,294,295] Mouse kidney transplant model Protective [298] Rat and mouse liver transplant model Protective [299], not involved [305] Mouse corneal transplant model Protective [300,304] Rat and mouse lung transplant models Protective [207,241] Rat and mouse cardiac transplant model Protective [301][302][303] Mouse bone marrow transplant model Protective [306,307] Mouse skin transplant model Protective [310] Chimaeric humanised mouse model of graft arteriosclerosis Rat monocrotaline-induced pulmonary hypertension Protective [54] Angiotensin II-induced vascular constriction in rats Protective [41] Angiotensin II-induced vascular constriction in mice Protective [54], harmful [183] LPS-induced endotoxaemia Protective [182] Cataracts Mice overexpressing human IDO1 in the lens Harmful [591] Bone remodelling Wild-type mice Protective [592,593] maintenance of self-tolerance under normal conditions. However, numerous studies with Ido1 gene-deficient mice or IDO1 inhibitors reveal that the enzyme plays an important role in the establishment of acquired immune tolerance upon exposure to new or foreign antigens.…”

Induction of Indoleamine 2,3-dioxygenase (IDO) Enzymatic Activity Contributes to Interferon-Gamma Induced Apoptosis and Death Receptor 5 Expression in Human Non-small Cell Lung Cancer Cells

“…Two possible mechanisms of apoptosis are proposed: 1) depletion of tryptophan (de la Maza and Peterson, 1988;Ozaki et al, 1988;Lee et al, 2002;Platten et al, 2012) and 2) production of toxic tryptophan metabolites in the kynurenine pathway, such as kynurenines and 3-hydroxyanthranilic (3-HAA) (Morita et al, 2001;Fallarino et al, 2003;Mailankot et al, 2009;Lee et al, 2010;Mailankot and Nagaraj, 2010;Song et al, 2011;Hou et al, 2014). In this study, we demonstrated that the addition of either the IDO inhibitor 1-MT or L-tryptophan could decrease IFN-γ-induced reduction of cell viability ( Figure 5A) and apoptosis ( Figure 5B-E).…”

UVA Light-excited Kynurenines Oxidize Ascorbate and Modify Lens Proteins through the Formation of Advanced Glycation End Products

“…To generate the double transgenic mice that specifically overexpressed hIDO and hSVCT2 in the lens epithelium and fiber cells, we cross-bred homozygous hIDO with homozygous hSVCT2 transgenic mice, both on a C57BL/6 background. The details for the hIDO mice have been published elsewhere (19). These animals contain high levels of kynurenines in the lenses.…”

“…The kynurenines in the mouse lens LMW fraction were determined using a GraceVydac C 18 column (4.6 ϫ 250 cm; 218TP54) in a high performance liquid chromatograph, which was run using a 0 -12% H 2 O-acetonitrile gradient at a flow rate of 0.8 ml/min with effluent monitoring at ex / em ϭ 360/480 nm, as described previously (19). Kyn, Nfk, and 3OHKyn standard curves were generated under the same conditions to establish the levels of the kynurenines in the LMW fractions.…”