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The Journal of Immunology, 2001, 166: 5374-5380.
Copyright © 2001 by The American Association of Immunologists

Engineering of Macrophages to Produce IFN-{gamma} in Response to Hypoxia1

Luca Carta*, Sandra Pastorino2,*, Giovanni Melillo{dagger}, Maria C. Bosco*, Stefano Massazza* and Luigi Varesio*

* Laboratory of Molecular Biology, G. Gaslini Institute, Genoa, Italy; and {dagger} Developmental Therapeutics Program Tumor Hypoxia Laboratory, Science ApplicationsInternational Corporation, National Cancer Institute, Frederick, MD 21702

Activation of murine macrophages (M{phi}) requires the collaboration of signals derived from the immune system and the environment. In this study, we engineered a murine M{phi} cell line to become activated in response to an environmental signal, hypoxia, as the sole stimulus. Hypoxia is a condition of low oxygen tension, occurring in several pathological tissues, which acts in synergy with IFN-{gamma} to induce full M{phi} activation. We transfected the ANA-1 murine M{phi} cell line with a construct containing the IFN-{gamma} gene controlled by a synthetic promoter inducible by hypoxia (HRE3x-Tk), and we characterized the cellular and molecular biology of the engineered M{phi} under normoxia or hypoxia. Engineered M{phi} in normoxia expressed basal levels of IFN-{gamma} mRNA and protein that were strongly augmented by shifting the cells to hypoxia. Furthermore, they responded to the synthesized IFN-{gamma} with induction of IFN-responsive factor-1 and 2'-5'-oligoadenylate synthase expression. Under normoxic conditions, the engineered M{phi} had a significant constitutive level of Ia Ags and Fc receptors. Hypoxia induced further augmentation of Ia and Fc expression. Finally, hypoxia induced inducible NO synthase expression, and subsequent reoxygenation led to the production of NO. In conclusion, the engineered M{phi}, which produce IFN-{gamma} in an inducible manner, express new biochemical and functional properties in response to low oxygen environment as the sole stimulus, thereby circumventing the need for costimulation by other immune system-derived signals.




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