These and additional reports (Miller, 2010) of altered T cells in depressive disorder led to demonstrations that T cells mediate the negative impact of depressive disorder on health outcomes in depressed patients with infectious diseases or cancer. Substantial evidence indicates that dysregulated GSK3 contributes to mood disorders (Li and Jope, 2010): brain GSK3 is abnormally active in postmortem human prefrontal cortex from depressed subjects (Karege et al., 2007), GSK3 is usually activated in mouse brain in the learned helplessness model of depressive disorder (Polter et al., 2010), antidepressants inhibit GSK3 (Li et al., 2004), reducing GSK3 activity ameliorates depression-like behaviors in rodents (Gould et al., 2003; Kaidanovich-Beilin et al., 2004; OBrien et al., 2004b; Beaulieu et al., 2008), and abnormally active GSK3 in GSK3 knockin mice increases susceptibility to depression-like behaviors (Polter et al., 2010). factors by GSK3 appears to play a prominent role in WAY 181187 its regulation of immune responses, including of NF-B, cyclic AMP response element binding protein, and signal transducer and activator of transcription-3. studies have shown that GSK3 inhibitors ameliorate clinical symptoms of both peripheral and central inflammatory diseases, particularly experimental autoimmune encephalomyelitis, the animal model of MS. Therefore, the development and application of GSK3 inhibitors may provide a new therapeutic strategy to reduce neuroinflammation associated with many central nervous system diseases. administration of GSK3 Rabbit polyclonal to HES 1 inhibitors provided protection from endotoxin shock sufficiently enough to allow the survival of most mice from an otherwise lethal (LD100) dose of lipopolysaccharide (LPS; Martin et al., 2005). This study showed for the first time the powerful ability of GSK3 inhibitors to shift the balance of the inflammatory response from pro-inflammatory to anti-inflammatory, and revealed the therapeutic potential for these drugs in inflammatory conditions (Martin et al., 2005). These findings raised the novel possibility that inhibitors of GSK3 may prove to be beneficial in conditions involving inflammation (Jope et al., 2007). The pro-inflammatory action of GSK3 and anti-inflammatory actions of its inhibitors have been demonstrated with a variety of inflammatory molecules and extended to several cell types (Gao et al., 2008; Wang et al., 2009a,b, 2011a; Gurrieri et al., 2010; Kao et al., 2010; Klamer et al., 2010; Baarsma et al., 2011; for review Beurel WAY 181187 et al., 2010), including cells in the CNS that contribute to neuroinflammation. In LPS-stimulated microglia, GSK3 promotes the production of WAY 181187 cytokines and other inflammatory molecules, such as IL-1, TNF, IL-6, IL-8, RANTES, CXCL-10, and nitric oxide (NO; Luna-Medina et al., 2005; Hashioka et al., 2007; Beurel and Jope, 2009b; Cheng et al., 2009; Huang et al., 2009; Yuskaitis and Jope, 2009). As in the periphery, NF-B is usually thought to be a critical transcription factor targeted by GSK3 for promoting neuroinflammation (Yuskaitis and Jope, 2009; Wang et al., 2010), as discussed below. In addition to microglia, GSK3 also promotes cytokine production by astrocytes (Park et al., 2006; Beurel and Jope, 2010), in particular IL-6, and promotes the IL-6/signal transducer and activator of transcription-3 (STAT3)-dependent activation of glial fibrillary acidic protein (GFAP), which is a critical marker of astrogliosis (Beurel and Jope, 2008, 2009b). Tolerance is usually a mechanism whereby cells dampen their response to two consecutive identical stimuli, and the promotion of IL-6 production by GSK3 was shown to also involve GSK3 counteracting LPS-induced tolerance for IL-6 production in astrocytes (Beurel and Jope, 2010). Besides regulating cytokine production in glia, GSK3 also promotes migration and activation of glial cells (Beurel and Jope, 2008; Yuskaitis and Jope, 2009). Inhibition of GSK3 promotes microglial survival during oxygenCglucose deprivation (Chong et al., 2007) and treatment with erythropoietin both inhibited GSK3 and supported microglia survival (Li et al., 2006), actions that may contribute to minimizing permanent CNS damage. Recently, inhibition of GSK3 was suggested to promote stabilization of the brain blood barrier (Ramirez et al., 2010). This was based on findings in cultured brain microvascular endothelial cells that GSK3 inhibition reduced the production of several inflammatory molecules and monocyte adhesion to and migration across cytokine-stimulated cells. Furthermore, inhibition of GSK3 reduced leukocyte adhesion to brain endothelium under inflammatory conditions. Pro-Inflammatory Mechanisms of GSK3 GSK3 can promote pro-inflammatory cytokine production through NF-B activation Regulation of the inflammatory transcription factor NF-B was found to be key for the pro-inflammatory actions of GSK3 (Martin et al., 2005; Gong et al., 2008a,b; Yuskaitis and Jope, 2009; Wang et al., 2010). Inhibitors of GSK3 reduced TLR-induced production of inflammatory cytokines by inhibiting the.
These and additional reports (Miller, 2010) of altered T cells in depressive disorder led to demonstrations that T cells mediate the negative impact of depressive disorder on health outcomes in depressed patients with infectious diseases or cancer