High expression of IMPACT protein promotes resistance to indoleamine 2,3-dioxygenase-induced cell death

• Published in: Journal of cellular physiology Vol. 225; no. 1; pp. 196 - 205
• Main Authors: Habibi, Darya, Jalili, Reza B., Forouzandeh, Farshad, Ong, Christopher J., Ghahary, Aziz
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.10.2010
• Subjects: Animals; Antiviral Agents - pharmacology; Cell Death - drug effects; Cells, Cultured; Coculture Techniques; Culture Media, Conditioned - chemistry; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - physiology; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase - pharmacology; Interferon-gamma - pharmacology; Jurkat Cells; Keratinocytes - cytology; Keratinocytes - physiology; Kynurenine - metabolism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins - genetics; Proteins - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction - physiology; T-Lymphocytes - cytology; T-Lymphocytes - physiology; Transcription Factor CHOP - genetics; Transcription Factor CHOP - metabolism; Tryptophan - deficiency
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.22220

Indoleamine 2,3‐dioxygenase (IDO), a tryptophan degrading enzyme, is a potent immunomodulatory factor. IDO expression in fibroblasts selectively induces apoptosis in immune cells but not in primary skin cells. However, the mechanism(s) of this selective effect of IDO‐induced low tryptophan environment is not elucidated. The aim of present study was to investigate whether the activity of general control non‐derepressible‐2(GCN2) kinase stress‐responsive pathway and its known inhibitor, protein IMPACT homolog, in immune and skin cells are differentially regulated in response to IDO‐induced low tryptophan environment. IDO‐expressing human fibroblasts were co‐cultured with Jurkat cells, human T cells, fibroblasts, or keratinocytes. Activation of GCN2 pathway was significantly higher in immune cells exposed to IDO‐expressing environment relative to that of skin cells. In contrast, IMPACT was highly and constitutively expressed in skin cells while its expression was very low in stimulated T cells and undetectable in Jurkat cells. A significant IDO‐induced suppressive as well as apoptotic effect was demonstrated in IMPACT knocked down fibroblasts co‐cultured with IDO‐expressing fibroblasts. Proliferation of Jurkat cells, stably transduced with IMPACT‐expressing vector, was rescued significantly in tryptophan‐deficient but not IDO‐expressing environment. This may be due to the ability of IMPACT to recover the effects of IDO‐mediated tryptophan depletion (GCN2 dependent) but not the effects of IDO‐generated cytotoxic metabolites. These findings collectively suggest for the first time that high expression of protein IMPACT homolog in non‐immune cells such as skin cells acts as a protective mechanism against IDO‐induced GCN2 activation, therefore, makes them resistant to the amino acid‐deprived environment caused by IDO. J. Cell. Physiol. 225: 196–205, 2010. © 2010 Wiley‐Liss, Inc.