Submitted June 16, 2006
Accepted September 25, 2006
GSK-3 mediates differentiation and activation of pro-inflammatory dendritic cells
Elena Rodionova, Michael Conzelmann, Eugene Maraskovsky*, Michael Hess, Michael Kirsch, Thomas Giese, Anthony D Ho, Margot Zoller, Peter Dreger, and Thomas Luft
German Cancer Research Center, Germany
CSL Limited, Australia
University of Heidelberg, Germany
* Corresponding author; email: eugene.maraskovsky{at}ludwig.edu.au.
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 (a) inhibits macrophage development during differentiation of DC, (b) is constitutively active in immature DC and suppresses spontaneous maturation, and (c) acquires a pro-inflammatory functional status mediating high levels of IL-12, IL-6 and TNF-
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 pro-inflammatory 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 pro-inflammatory DC differentiation and activation.
