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in Response to Hypoxia1
*
Laboratory of Molecular Biology, G. Gaslini Institute, Genoa, Italy; and
Developmental Therapeutics Program Tumor Hypoxia Laboratory, Science ApplicationsInternational Corporation, National Cancer Institute, Frederick, MD 21702
Activation of murine macrophages (M
) requires the collaboration
of signals derived from the immune system and the environment. In this
study, we engineered a murine M 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-
to induce full
M activation. We transfected the ANA-1 murine M cell line with a
construct containing the IFN- gene controlled by a synthetic
promoter inducible by hypoxia (HRE3x-Tk), and we characterized the
cellular and molecular biology of the engineered M under normoxia or
hypoxia. Engineered M in normoxia expressed basal levels of IFN-
mRNA and protein that were strongly augmented by shifting the cells to
hypoxia. Furthermore, they responded to the synthesized IFN- with
induction of IFN-responsive factor-1 and 2'-5'-oligoadenylate synthase
expression. Under normoxic conditions, the engineered M 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, which
produce IFN- 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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