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Picolinic acid- or desferrioxamine-inducible autocrine activation of macrophages engineered to produce IFN gamma: an approach for gene therapy

  1. Author:
    Pastorino, S.
    Carta, L.
    Puppo, M.
    Melillo, G.
    Bosco, M. C.
    Varesio, L.

  2. Author Address

    Varesio, L, G Gaslini Inst Children, Mol Biol Lab, Lgo G Gaslini 5, I-16147 Genoa, Italy G Gaslini Inst Children, Mol Biol Lab, I-16147 Genoa, Italy. NCI, DTP Tumor Hypoxia Program, NIH, Frederick, MD 21701 USA.
    1. Year: 2004
  2. Journal: Gene Therapy
    1. 11
    2. 6
    3. Pages: 560-568
  4. Type of Article: Article
  1. Abstract:

    Macrophage (Mphi)-based vectors are highly mobile cellular shuttles designed to deliver therapeutic genes within the tissues. We engineered a mouse Mf cell line to express the murine interferon-gamma (IFNgamma) under the control of an inducible promoter containing the hypoxia-responsive element, which can be triggered by hypoxia and other stimuli. We show that this Mphi vector can be induced to produce IFNgamma under normoxic conditions by stimulation with picolinic acid (PA), a catabolite of tryptophan, or desferrioxamine (DFX), an iron-chelating drug. The Mphi vector responds to IFNgamma with the induction of IRF-1 and of other IFNgamma-inducible genes, the expression of Ia antigens and induction of phagocytic activity. Inducible nitric oxygen synthase gene expression, nitric oxide production, as well as TNFalpha secretion were enhanced by PA or DFX as the sole stimuli. None of the above responses could be triggered individually by PA or DFX in control, normal Mphi, indicating that the Mphi vector overcame the need for costimulatory molecules derived from the immune system for its full activation. Furthermore, we demonstrate that extracellular iron can downregulate such response, thereby identifying an additional tool for the fine tuning of the Mphi vector response to stimulation

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