GSK-3 mediates differentiation and activation of proinflammatory dendritic cells

Rodionova, E., et al. 2007. Blood 109, 1584-1592

Student: Jui-In Kai (蓋如茵)                                    Time: 14:00~15:00, Dec. 12, 2007

Commentator: Yee-Shin Lin (林以行教授)               Place: Room 601

Abstract

Dendritic cells (DCs), the most potent antigen-presenting cells, play a critical role in immune responses by interacting with and activating naive T cells. In addition to the different expression of surface markers, DCs may also secrete high levels of proinflammatory cytokines and chemokines if appropriately stimulated with immune cells or activators (1). Immature human monocyte-derived DCs (MoDCs) are able to make the development of diverse functional DC phenotypes while MoDCs stimulated with pathogens or cytokines. However, the key mechanisms/molecules required for proinflammatory DCs differentiated from immature MoDCs are still unidentified. Glycogen synthase kinase-3 (GSK-3), a multifunctional enzyme, is involved in and critical for cellular growth, differentiation, apoptosis, and inflammation (2). Inhibiting GSK-3 sustains anti-apoptosis and anti-inflammation and regulates the production of proinflammatory cytokines. In the present paper (3), the authors investigate the roles of GSK-3 in the differentiation and activation of proinflammatory DCs. They found that inhibiting GSK-3 promoted macrophage-like but not DCs differentiation from MoDCs and caused spontaneous maturation of MoDCs. In these cells, the phagocytic activity, surface markers, and the expression profile of cytokines are different from DCs or MoDCs. Since GSK-3 constitutively activated in MoDCs, however, it was partially inactivated via PI3K/Akt-regulated pathway during DCs maturation and activation. Moreover, GSK-3 was required for IL-12p70 secretion and enhanced IL-12p40, IL-6, and TNF-a, but not IL-10, secretion by DCs activated with E. coli or CD40L. Meanwhile, GSK-3 was specifically crucial for migration of E. coli-activated DCs. The involvement of PI3K/Akt/GSK-3 signaling in controlling IL-12 and IL-10 expression was also demonstrated. GSK-3 specially increased IL-12p35 but decreased IL-10 mRNA expression in MoDCs. Taken together, GSK-3 plays the activating and inhibitory roles in differentiation and activation of proinflammatory DCs and in maintenance of immature phenotype of DCs.

References

1.      Luft, T., et al. 2006. Adaptive functional differentiation of dendritic cells: integrating the network of extra- and intracellular signals. Blood 107, 4763-4769

2.      Frame, S., et al. 2001. GSK3 takes centre stage more than 20 years after its discovery. Biochem. J. 359, 1-16

3.      Rodionova, E., et al. 2007. GSK-3 mediates differentiation and activation of proinflammatory dendritic cells. Blood 109, 1584-1592