GSK-3 mediates differentiation and activation of proinflammatory dendritic cells

Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany
Blood (Impact Factor: 10.43). 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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    • "GSK3 is constitutively active in DCs and suppresses their spontaneous maturation, as shown by increased expression of costimulatory molecules CD80, CD83 and CD86 and higher levels of IL-6 secretion upon pharmacological inhibition of GSK3 with LiCl [27]. Upon DC activation in response to a variety of TLR agonists, GSK3 attains a proinflammatory status mediating production of proinflammatory IL-12, IL-6, TNFa, IL-1b, and IFNc and negatively regulating the production of anti-inflammatory IL-10 [11] [17] [26] [27]. Accordingly, administration of a GSK3 inhibitor has been shown to suppress a Th1-mediated immune response against Contents lists available at SciVerse ScienceDirect "
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    ABSTRACT: The function of dendritic cells (DCs) is modified by glycogen synthase kinase GSK3 and GSK3 inhibitors have been shown to protect against inflammatory disease. Regulators of GSK3 include the phosphoinositide 3 kinase (PI3K) pathway leading to activation of protein kinase B (PKB/Akt) and serum and glucocorticoid inducible kinase (SGK) isoforms, which in turn phosphorylate and thus inhibit GSK3. The present study explored, whether PKB/SGK-dependent inhibition of GSK3 contributes to the regulation of cytosolic Ca(2+) concentration following stimulation with bacterial lipopolydasscharide (LPS). To this end DCs from mutant mice, in which PKB/SGK-dependent GSK3α,ß regulation was disrupted by replacement of the serine residues in the respective SGK/PKB-phosphorylation consensus sequence by alanine (gsk3(KI)), were compared to DCs from respective wild type mice (gsk3(WT)). According to Western blotting, GSK3 phosphorylation was indeed absent in gsk3(KI) DCs. According to flow cytometry, expression of antigen-presenting molecule major histocompatibility complex II (MHCII) and costimulatory molecule CD86, was similar in unstimulated and LPS (1 μg/ml, 24 h)-stimulated gsk3(WT) and gsk3(KI) DCs. Moreover, production of cytokines IL-6, IL-10, IL-12 and TNFα was not significantly different in gsk3(KI) and gsk3(WT) DCs. In gsk3(WT) DCs, stimulation with LPS (1 μg/ml) within 10 min led to transient phosphorylation of GSK3. According to Fura2 fluorescence, bacterial lipopolysaccharides (LPS, 1 μg/ml) increased cytosolic Ca(2+) concentration, an effect significantly more pronounced in gsk3(KI) DCs than in gsk3(WT) DCs. Conversely, GSK3 inhibitor SB216763 (3-[2,4-Dichlorophenyl]-4-[1-methyl-1H-indol-3-yl]-1H-pyrrole-2,5-dione, 10 μM, 30 min) significantly blunted the increase of cytosolic Ca(2+) concentration following LPS exposure. In conclusion, PKB/SGK-dependent GSK3α,ß activity participates in the regulation of Ca(2+) signaling in dendritic cells.
    Biochemical and Biophysical Research Communications 06/2013; 437(3). DOI:10.1016/j.bbrc.2013.06.075 · 2.28 Impact Factor
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    • "Glycogen synthase kinase-3 (GSK-3) was first identified as a key regulator of the glycogen metabolism; it regulates various cellular processes such as apoptosis, differentiation, growth, cell motility, and embryonic development by modulating various substrates (Cohen and Frame, 2001; Woodgett, 2001; Jope and Johnson, 2004). Recent studies have shown the role of GSK-3 as a regulator of immune responses, including activation and differentiation of DCs and endotoxemia (Rodionova et al., 2007; Noh et al., 2011). "
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    Experimental and Molecular Medicine 02/2012; 44(5):340-9. DOI:10.3858/emm.2012.44.5.038 · 2.46 Impact Factor
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    • "Microglia are known to accumulate around A β plaques in AD (Christie et al. , 1996 ; Joshi and Crutcher 1998 ; Stalder et al. , 1999 ) and there is increased expression of infl ammatory mediators in AD brain tissue (McGeer and McGeer , 1996 ). In the periphery, the regulation of GSK3 activity is crucial for infl ammatory cell differentiation , infl ammatory cell migration, and the secretion of proinfl ammatory cytokines (Woodgett and Ohashi , 2005 ; Jope et al. , 2007 ; Rodionova et al. , 2007 ). Owing to the capacity of GSK3 to differentially control the production of interleu- kin-10 (IL-10) and IL-12, Ohtani et al. set forth to determine the in vivo effects of GSK3 inhibition by assessing the ability of GSK3 to alter Th1-and Th2-responses in mice using a Leishmania major infection model (Ohtani et al. , 2008 ). "
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    ABSTRACT: As a constitutively active kinase, glycogen synthase kinase 3 (GSK3) is a kinase which regulates body metabolism by phosphorylation of glycogen synthase (GS) and other substrates. Considerable evidence suggests that GSK3 is involved in the common pathology underlying Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). The overexpression or overactivation of GSK3 could induce a series of pathological changes, most of which are hallmarks of AD and T2DM. Therefore, GSK3 could be a novel target to treat these two age-dependent diseases. The inhibition of this kinase can prevent the aggregation of β-amyloid (Aβ) and hyperphosphorylation of tau protein. GSK3 inhibition can also be a promising strategy to ameliorate neurodegenerative developments. Its potential association with memory formation has been shown in electrophysiological and behavioral experiments. The neuroprotective effects of novel drugs developed to treat T2DM, glucagon-like peptide 1 (GLP-1) and its long-lasting analogs, have a possible link to GSK3 modification. Recent investigations of the interaction between the phosphatidylinositol 3 kinase (PI3K) signaling pathway and the protective effect of novel GPL-1 receptor agonist geniposide on PC12 cells support this theory.
    Reviews in the neurosciences 02/2012; 23(1):1-11. DOI:10.1515/rns.2011.061 · 3.31 Impact Factor
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