Induction of indoleamine-2,3-dioxygenase in head/neck-squamous-cell-carcinoma by an interferon gamma-independent mechanism

Objectives: Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme in the L-tryptophan-kynurenine pathway which converts an essential amino acid, L-tryptophan, to N-formylkynurenine. Although recent studies have suggested that IDO expression by several stimuli including lipopolysaccharides (LPS) and interferon-g (IFN-g) is mediated through IFN-g dependent and independent mechanisms, the mechanisms of anti-cancer agents induced expression of IDO in head and neck squamous cell carcinoma (HNSCC) still remain unknown.

Methods: Real Time PCR (RT-PCR), Western blot analysis, in vitro kinase assay and electrophoretic mobility shift assay (EMSA).

Results: In this study, both Anti-Fas antibody (CH11) and Tumor Necrosis Factor alpha (TNF-a)induced the expression of IDO triggered cell death in both HNSCC cell lines CLS-354 and SCC nasal septum. CH11 and TNF-a induced cell death was associated with the induction of IDO gene transcription and the activation of both JNK and NF-kB pathways. Interestingly, the inhibition of CH11 and TNF-a induced IDO expression by JNK (SP600125) and NF-kB (Bay11-7082) inhibitors, but not by JAK1 inhibitor, suggesting the involvement of IFN-g independent mechanism in the regulation of CH11 and TNF-a induced IDO transcription in HNSCC cells.

Conclusion: Our data demonstrate for the first time the regulation of CH11 and TNF-a induced expression of IDO in HNSCC cells by an IFN-g independent mechanism.