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

Abstract

Interferon-gamma (IFN-γ) has been used to treat various malignant tumors. However, the molecularmechanisms underlying the direct anti-proliferative activity of IFN-γ are poorly understood. In the present study,we examined the in vitro antitumor activity of IFN-γ on two human non-small-cell lung carcinoma (NSCLC) celllines, H322M and H226. Our findings indicated that IFN-γ treatment caused a time-dependent reduction in cellviability and induced apoptosis through a FADD-mediated caspase-8/tBid/mitochondria-dependent pathway inboth cell lines. Notably, we also postulated that IFN-γ increased indoleamine 2,3-dioxygenase (IDO) expressionand enzymatic activity in H322M and H226 cells. In addition, inhibition of IDO activity by the IDO inhibitor1-MT or tryptophan significantly reduced IFN-γ-induced apoptosis and death receptor 5 (DR5) expression,which suggests that IDO enzymatic activity plays an important role in the anti-NSCLC cancer effect of IFN-γ.These results provide new mechanistic insights into interferon-γ antitumor activity and further support IFN-γas a potential therapeutic adjuvant for the treatment of NCSLC