Article

GSK-3 mediates differentiation and activation of proinflammatory dendritic cells.

Department of Molecular Oncology/Hematology, German Cancer Research Center, Heidelberg, Germany.
Blood (impact factor: 9.9). 03/2007; 109(4):1584-92. DOI:10.1182/blood-2006-06-028951 pp.1584-92
Source: PubMed

ABSTRACT 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-alpha 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.

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Keywords

DC activation
 
dendritic cells
 
glycogen synthase kinase 3
 
GSK-3 enhances IL-12p35 mRNA expression
 
human monocyte-derived DC differentiation
 
inhibitory effects
 
inhibitory pathways
 
inhibits IL-10
 
intracellular molecular network
 
key components
 
key integrator
 
kinases priming GSK-3 targets
 
proinflammatory cytokine IL-12p70
 
proinflammatory DC differentiation
 
proinflammatory functional status mediating
 
specific function
 
study investigates
 
suppresses spontaneous maturation
 
TNF-alpha secretion
 
vitro model