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Published online before print September 12, 2007

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(Journal of Leukocyte Biology. 2007;82:1446-1454.)
© 2007 by Society for Leukocyte Biology

Modulation of dendritic cell differentiation by colony-stimulating factor-1: role of phosphatidylinositol 3'-kinase and delayed caspase activation

Agnes S. Lo^*,1, Patricia Gorak-Stolinska^*, Véronique Bachy^*, Mohammad A. Ibrahim^*, David M. Kemeny^* and John Maher^*,

^* Department of Allergy and Clinical Immunology, King’s College Hospital NHS Foundation Trust, and
King’s College London, Breast Cancer Biology Group, Division of Cancer Studies, Guy’s Hospital Campus, London, United Kingdom

¹Correspondence at current address: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Jimmy Fund Building, Room 707, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. E-mail: agnes_lo{at}dfci.harvard.edu

Monocytes acquire a dendritic cell (DC) phenotype when cultured with GM-CSF and IL-4. By contrast, CSF-1 is a potent inducer of monocyte-to-macrophage differentiation. Increasing evidence indicates that DC development is impaired in conditions characterized by CSF-1 overproduction, including pregnancy, trauma, and diverse malignancies. To study this, we have exposed newly established monocyte-derived DC cultures to conditions of CSF-1 excess. As a consequence, differentiation is skewed toward a unique intermediate phenotype, which we have termed DC-M. Such cells exhibit macrophage-like morphology with impaired allostimulatory capacity, altered cytokine production, and a distinctive cell surface immunophenotype. In light of the emerging role of caspase activation during macrophage differentiation, the activity of caspases 3, 8, and 9 was examined in DC and DC-M cultures. It is striking that DC-M cultures exhibit a delayed and progressive increase in activation of all three caspases, associated with depolarization of mitochondrial membrane potential. Furthermore, when DC-M cultures were supplemented with an inhibitor of caspase 8 or caspase 9, impairment of DC differentiation by CSF-1 was counteracted. To investigate upstream regulators of caspase activation in DC-M cultures, experiments were performed using inhibitors of proximal CSF-1 receptor signaling. These studies demonstrated that the PI-3K inhibitors, wortmannin and LY294002, antagonize the ability of CSF-1 to inhibit DC differentiation and to promote caspase activation. Together, these data identify a novel, PI-3K-dependent pathway by which CSF-1 directs delayed caspase activation in monocytes and thereby modulates DC differentiation.

Key Words: macrophage • monocyte • apoptosis

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