Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3)

Abstract

In just a few years, the view of glycogen synthase kinase-3 (GSK3) has been transformed from an obscure enzyme seldom encountered in the immune literature to one implicated in an improbably large number of roles. GSK3 is a crucial regulator of the balance between pro- and anti-inflammatory cytokine production in both the periphery and the central nervous system, so that GSK3 inhibitors such as lithium can diminish inflammation. GSK3 influences T-cell proliferation, differentiation and survival. Many effects stem from GSK3 regulation of critical transcription factors, such as NF-kappaB, NFAT and STATs. These discoveries led to the rapid application of GSK3 inhibitors to animal models of sepsis, arthritis, colitis, multiple sclerosis and others, demonstrating their potential for therapeutic intervention.

Box 1 figure

The activity of the GSK3 isoforms α and β are regulated by phosphorylation of serine 21 and 9 respectively. Lithium is the best characterized pharmacological inhibitor of GSK3 activity.

Figure 1

NF-κB, CREB, and AP-1 transcription factor regulation by GSK3. GSK3 regulates the activities of over 20 transcription factors, including several that are important for immune function. NF-κB is a key inflammatory transcription factor, but the GSK3 regulatory influences on NF-κB are complex due to cell-selective, stimulus-selective, and promoter-selective interactions that can be stimulatory or inhibitory (reviewed in [66]). GSK3 is required for NF-κB-mediated expression of several proinflammatory cytokines [3,16]. Promoter-selective regulation of NF-κB has been demonstrated wherein GSK3 is required for expression of IL-6 and monocyte chemoattractant protein-1 (MCP-1/CCL2), but not of IκBα and macrophage inflammatory protein-2 (MIP-2/CXCL2) [67]. In certain conditions, GSK3 can also inhibit NF-κB [68], and GSK3-mediated phosphorylation of p65-NF-κB promotes the docking of Nurr1 and the CoREST corepressor complex to reduce stimulated NF-κB transcriptional activity to the basal level [69]. Thus, the effects of GSK3 on NF-κB are context-specific, and involve both activation and subsequent feedback inhibition of NF-κB activity. GSK3 dampens the production of anti-inflammatory IL-10 by suppressing transcriptional activity of CREB and AP-1, both of which contribute to IL-10 expression [3,8]. The opposing effects of GSK3 on pro- and anti-inflammatory cytokines are at least partially mediated by competition between NF-κB and CREB for the co-activator CREB-binding protein (CBP), which is well-known to be present in limited amounts and for which transcription factors compete. Red arrows signify actions regulated by GSK3.

Figure 2

GSK3 regulation of STATs, Smads, β-catenin, and NFAT. Among the signal transducer and activator of transcription (STAT) family of transcription factors that are critical mediators of responses to cytokines and growth factors, GSK3 selectively promotes STAT3 and STAT5 activation [5,46,49]. Thus, regulation of transcription factors by GSK3 modulates both the expression of inflammatory molecules and cellular responses stimulated by cytokines. GSK3 also regulates Smad transcription factors that transduce signals generated by TGF-β and other stimulants of cell surface receptors to regulate gene expression [70-72]. The transcriptional co-activator β-catenin is phosphorylated by GSK3 in the Wnt signaling pathway, which targets β-catenin for proteosomal degradation. Inhibitors of GSK3 or activation of Wnt signaling induce stabilization of β-catenin that leads to its nuclear transport and accumulation to promote Tcf/LEF-mediated transcription. β-catenin also modulates activities of other transcription factors. For example, β-catenin negatively regulates bacteria-induced inflammation by inhibiting NF-κB [73], providing an indirect mechanism for GSK3 to promote NF-κB activity by down-regulating β-catenin. Increased β-catenin activity often contributes to the proliferation and survival of immune cells. β-catenin levels are low in unstimulated B cells, but B cell receptor activation triggers accumulation of β-catenin after inducing inhibition of GSK3 [74]. The T cell receptor (TCR) activates the NFATc (nuclear factor of activated T cells) family of transcription factors that promote antigenic and tolerogenic genetic programs. TCR signals induce nuclear localization of NFAT and GSK3 inactivates NFATc by phosphorylation-dependent stimulation of NFATc nuclear export [75]. Therefore, inhibition of GSK3 keeps NFATc active, mimicking the CD28 costimulatory signal for T cell proliferation [26,29,31]. Red arrows signify actions regulated by GSK3.