Article

GSK-3 mediates differentiation and activation of proinflammatory dendritic cells

Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany
Blood (Impact Factor: 10.45). 03/2007; 109(4):1584-92. DOI: 10.1182/blood-2006-06-028951
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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Available from: Anthony Ho, Apr 30, 2015
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    • "Interestingly, the changes of the IFNβ and IL-10 showed similar trends in BMDMs and BMDCs. Since our previous studies have demonstrated that GSK3β negatively regulates IFNβ and IL-10[12,13], and GSK3β is also critical for the development and maturation of BMDCs[59], we postulate that the expression level of GSK3β could be responsible for the distinct effects of Syk on IFNβ production in BMDCs and BMDMs. Silencing of Syk in BMDMs, unlike in BMDCs, decreased phosphorylation of GSK3β upon LPS stimulation (Supplemental Fig. 1E), suggesting that altered levels of GSK3β in Syk-deficient macrophages, resulting from signaling possibly independent of PI3K, could be the reason for the distinct effects of Syk on the production of IFNβ in BMDMs. "
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    • "In A and D, single and double asterisk represents P < 0.05 and P < 0.005, respectively. JOURNAL OF CELLULAR BIOCHEMISTRY GLYCOGEN SYNTHASE KINASE 3 INCREASES IL-1B INDUCED NO with other cell types [Martin et al., 2005; Rodionova et al., 2007; Rådinger et al., 2009] "
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