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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1584-1592. Prepublished online as a Blood First Edition Paper on October 10, 2006; DOI 10.1182/blood-2006-06-028951.
IMMUNOBIOLOGY GSK-3 mediates differentiation and activation of proinflammatory dendritic cells1 Department of Molecular Oncology/Hematology and 5 Department of Tumor Progression and Immune Defense, German Cancer Research Center, Heidelberg, Germany; 2 Department Medicine V and 3 Institute of Immunology, University of Heidelberg, Germany; 4 CSL Limited, Melbourne, Australia
The key components of the intracellular molecular network required for the expression of a specific function of dendritic cells (DCs) are as yet undefined. Using an in vitro model of human monocyte-derived DC differentiation, this study investigates the role of glycogen synthase kinase 3 (GSK-3), a multifunctional enzyme critical for cellular differentiation, apoptosis, self-renewal, and motility, in this context. We demonstrate that GSK-3 (1) inhibits macrophage development during differentiation of DCs, (2) is constitutively active in immature DCs and suppresses spontaneous maturation, and (3) acquires a proinflammatory functional status mediating high levels of IL-12, IL-6, and TNF-
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
secretion, and partially inhibits IL-10 in the context of DC activation. In particular, GSK-3 enhances IL-12p35 mRNA expression and thus the production of the proinflammatory cytokine IL-12p70 by integrating the activities of other kinases priming GSK-3 targets and the inhibitory effects of Akt-1. GSK-3 may therefore act as a key integrator of activating and inhibitory pathways involved in proinflammatory DC differentiation and activation. 
