GSK-3 mediates differentiation and activation of proinflammatory dendritic cells.
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.
Rodionova
Elena
E
Department of Molecular Oncology/Hematology, German Cancer Research Center, Heidelberg, Germany.
Conzelmann
Michael
M
Maraskovsky
Eugene
E
Hess
Michael
M
Kirsch
Michael
M
Giese
Thomas
T
Ho
Anthony D
AD
Zöller
Margot
M
Dreger
Peter
P
Luft
Thomas
T
D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D018664:Interleukin-12 / Q000235:genetics; D007378:Interleukins / Q000235:genetics; D008264:Macrophages / Q000166:cytology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3