Glycogen synthase kinase 3: A point of convergence for the host inflammatory response

Wang, Huizhi; Brown, Jonathan R.; Martin, Michael

doi:10.1016/j.cyto.2010.10.009

Cited by 201 publications

(202 citation statements)

References 128 publications

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“…Studies in our laboratory have shown that glycogen synthase kinase (GSK)-3b has a suppressive role on SHP2 phosphorylation, while pharmacologically inhibiting GSK-3b facilitated SHP2 activation followed by SHP2-mediated IFN-g resistance (36,65). Notably, in H. pylori infection, PI3K/Akt signaling may inactivate GSK-3b followed by b-catenin stabilization to promote gastric tumorigenesis (66,67).…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori Infection Activates Src Homology-2 Domain–Containing Phosphatase 2 To Suppress IFN-γ Signaling

Wang

Chen

Sheu

et al. 2014

The Journal of Immunology

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Helicobacter pylori infection not only induces gastric inflammation but also increases the risk of gastric tumorigenesis. IFN-γ has antimicrobial effects; however, H. pylori infection elevates IFN-γ–mediated gastric inflammation and may suppress IFN-γ signaling as a strategy to avoid immune destruction through an as-yet-unknown mechanism. This study was aimed at investigating the mechanism of H. pylori–induced IFN-γ resistance. Postinfection of viable H. pylori decreased IFN-γ–activated signal transducers and activators of transcription 1 and IFN regulatory factor 1 not only in human gastric epithelial MKN45 and AZ-521 but also in human monocytic U937 cells. H. pylori caused an increase in the C-terminal tyrosine phosphorylation of Src homology-2 domain–containing phosphatase (SHP) 2. Pharmacologically and genetically inhibiting SHP2 reversed H. pylori–induced IFN-γ resistance. In contrast to a clinically isolated H. pylori strain HP238, the cytotoxin-associated gene A (CagA) isogenic mutant strain HP238CagAm failed to induce IFN-γ resistance, indicating that CagA regulates this effect. Notably, HP238 and HP238CagAm differently caused SHP2 phosphorylation; however, imaging and biochemical analyses demonstrated CagA-mediated membrane-associated binding with phosphorylated SHP2. CagA-independent generation of reactive oxygen species (ROS) contributed to H. pylori–induced SHP2 phosphorylation; however, ROS/SHP2 mediated IFN-γ resistance in a CagA-regulated manner. This finding not only provides an alternative mechanism for how CagA and ROS coregulate SHP2 activation but may also explain their roles in H. pylori–induced IFN-γ resistance.

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Section: Discussionmentioning

confidence: 99%

Helicobacter pylori Infection Activates Src Homology-2 Domain–Containing Phosphatase 2 To Suppress IFN-γ Signaling

Wang

Chen

Sheu

et al. 2014

The Journal of Immunology

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“…Recent studies have identified GSK3 as a point of convergence for numerous cell-signaling pathways involved in a multitude of cellular physiological processes including development, cell cycle, differentiation, motility, microtubule function, apoptosis, adhesion, and inflammation (Doble and Woodgett 2003;Jope and Johnson 2004;Kockeritz et al 2006;Wang et al 2011c) (Fig. 1).…”

Section: What Is Gsk3 and How Does It Work?mentioning

confidence: 99%

“…It has been reported that GSK3b plays a central role in inflammation control by regulating the innate and adaptive immune responses (Wang et al 2011c). Since the pivotal role of inflammation in the development of cancer has been established, we will discuss the effect of inflammation in the development of EC and how GSK3b contributes to this process via regulating the activity and expression of inflammation mediators.…”

Section: Potential Involvement Of Gsk3 In the Progression Of Ec Via Tmentioning

confidence: 99%

“…As a substrate of the PI3K/Akt pathway, our lab has demonstrated that GSK3 plays a critical role in regulating the nature and magnitude of innate and adaptive immune response (Rehani et al 2009;Wang et al 2008Wang et al , 2011c. In this regard, inhibition of GSK3b was demonstrated to suppress innate immune responses by reducing the production of IL-1b, IL-6, tumor necrosis factor (TNF), and IL-12 while concurrently enhancing the production of IL-10, IL-1 receptor antagonist (IL-1Ra), interferon (IFN)-b, and IFN-b induced IL-10 in TLRs-stimulated cells (Rehani et al 2009;Wang et al 2008Wang et al , 2011a.…”

Section: Regulation Of Gsk3 In Inflammatory Responsesmentioning

confidence: 99%

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The Role of Glycogen Synthase Kinase 3-β in Immunity and Cell Cycle: Implications in Esophageal Cancer

Gao

Brown

Wang

et al. 2013

Arch. Immunol. Ther. Exp.

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Esophageal cancer (EC) is one of the most aggressive gastrointestinal malignancies, possessing an insidious onset and a poor prognosis. Numerous transcription factors and inflammatory mediators have been reported to play a pivotal role in the initiation and progression of this cancer. However, the specifics of the signaling network responsible for said factors, especially which elements are the critical regulators, are still being elucidated. Glycogen synthesis kinases 3 (GSK3)b was originally regarded as a kinase regulating glucose metabolism. Accumulating evidence demonstrated that it also played an essential role in a variety of cellular processes including proliferation, differentiation, inflammation, motility, and survival by regulating various transcription factors such as c-Jun, AP-1, b-catenin, CREB, and NF-jB. Aberrant regulation of GSK3b has been shown to promote cell growth in some cancers, while suppressing it in others, and thus may play an important role in the development of EC. This review will discuss our current understanding of GSK3b signaling, and its control of the expression and activation of various transcription factors that mediate the inflammatory response. We will also explore some of the known mediators of EC progression, and based on current literature, elucidate the potential roles and implications of GSK3 in this disease.

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“…The proapoptotic and proinflammatory properties of GSK-3 have also been demonstrated in various animal models of inflammation, including experimental lung injury, shock, spinal cord trauma, arthritis, ischemia/reperfusion injury, infection, asthma, colitis, renal failure, and hepatotoxicity (36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50). GSK-3 is currently a known regulator of IFN-g signaling and is involved in IFN-g-induced inflammatory activation (51)(52)(53)(54)(55)(56)(57)(58)(59). Previous studies performed by ourselves and others identified a proinflammatory role for GSK-3 and found that inhibiting GSK-3 provides cellular protection against IFN-g (54-56)-, TNF-a (60)-, and LPS-induced inflammation in vitro (61)(62)(63) and multiple organ failure in vivo (46,47,49,63).…”

mentioning

confidence: 99%

Glycogen Synthase Kinase-3 Facilitates Con A-Induced IFN-γ–Mediated Immune Hepatic Injury

Tsai

Huang

Chen

et al. 2011

The Journal of Immunology

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Immune hepatic injury induced by Con A results primarily from IFN-g-mediated inflammation, followed by hepatic cell death. Glycogen synthase kinase (GSK)-3, which acts proapoptotically and is proinflammatory, is also important for facilitating IFN-g signaling. We hypothesized a pathogenic role for GSK-3 in Con A hepatic injury. Con A stimulation caused GSK-3 activation in the livers of C57BL/6 mice. Inhibiting GSK-3 reduced Con A hepatic injury, including hepatic necrosis and apoptosis, inflammation, infiltration of T cells and granulocytes, and deregulated expression of adhesion molecule CD54. Con A induced hepatic injury in an IFN-g receptor 1-dependent manner. Con A/IFN-g induced activation and expression of STAT1 in a GSK-3-dependent manner. GSK-3 facilitated IFN-g-induced inducible NO synthase, but had limited effects on CD95 upregulation and CD95-mediated hepatocyte apoptosis in vitro. Notably, inhibiting GSK-3 decreased Con A-induced IFN-g production in both wild-type and IFN-g receptor 1-deficient C57BL/6 mice. In Con A-activated NKT cells, GSK-3 was also activated and was required for nuclear translocation of T-box transcription factor Tbx21, a transcription factor of IFN-g, but it was not required for CD95 ligand expression or activation-induced cell death. These results demonstrate the dual and indispensable role of GSK-3 in Con A hepatic injury by facilitating IFN-g-induced hepatopathy.

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Glycogen synthase kinase 3: A point of convergence for the host inflammatory response

Cited by 201 publications

References 128 publications

Helicobacter pylori Infection Activates Src Homology-2 Domain–Containing Phosphatase 2 To Suppress IFN-γ Signaling

Helicobacter pylori Infection Activates Src Homology-2 Domain–Containing Phosphatase 2 To Suppress IFN-γ Signaling

The Role of Glycogen Synthase Kinase 3-β in Immunity and Cell Cycle: Implications in Esophageal Cancer

Glycogen Synthase Kinase-3 Facilitates Con A-Induced IFN-γ–Mediated Immune Hepatic Injury

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