Article

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
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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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    • "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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    • "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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