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Role of glycogen synthase kinase-3 beta in the inflammatory response caused by bacterial pathogens Cortés-Vieyra, Ricarda; Bravo-Patiño, Alejandro; Valdez-Alarcón, Juan J; Juárez, Marcos C; Finlay, B B; Baizabal-Aguirre, Víctor M Jun 12, 2012

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REVIEW Open AccessRole of glycogen synthase kinase-3 beta inthe inflammatory response caused bybacterial pathogensRicarda Cortés-Vieyra1, Alejandro Bravo-Patiño1, Juan J Valdez-Alarcón1, Marcos Cajero Juárez1, B Brett Finlay2 andVíctor M Baizabal-Aguirre1,3*AbstractGlycogen synthase kinase 3β (GSK3β) plays a fundamental role during the inflammatory response induced bybacteria. Depending on the pathogen and its virulence factors, the type of cell and probably the context in whichthe interaction between host cells and bacteria takes place, GSK3β may promote or inhibit inflammation. The goalof this review is to discuss recent findings on the role of the inhibition or activation of GSK3β and its modulation ofthe inflammatory signaling in monocytes/macrophages and epithelial cells at the transcriptional level, mainlythrough the regulation of nuclear factor-kappaB (NF-κB) activity. Also included is a brief overview on theimportance of GSK3 in non-inflammatory processes during bacterial infection.Keywords: GSK3β, NF-κB, Inflammation, Virulence factors, Bacterial infectionBackgroundGlycogen synthase kinase 3 (GSK3), in its two isoformsGSK3α and GSK3β, is a multifunctional Ser/Thr kinasefound in eukaryotes [1]. This enzyme phosphorylatesand regulates the function of more than 50 substrates[2] and it is a point of convergence for numerous cell-signaling pathways involved in various essential cellularfunctions, such as glycogen metabolism, cell cycle con-trol, apoptosis, embryonic development, cell differenti-ation, cell motility, microtubule function, cell adhesionand inflammation [1-3]. The view of GSK3β has changedfrom an obscure metabolic kinase to an enzyme that pro-foundly regulates many components of the innate andadaptive immune systems. The broad array of immuneactions affected by GSK3β is partly attributable to the re-markable number of crucial transcription factors that itregulates [4]. The main objective of this review is to showthe importance of GSK3β in innate immunity againstbacterial infections through regulation of the inflamma-tory response induced by virulence factors.General properties of GSK3There are two major mammalian GSK3 protein isoforms(α and β) encoded by two distinct genes (gsk3α andgsk3β) [5] that are highly homologous within their kinasedomains (approximately 98% of identity), but with only36% identity in the last 76 C-terminal amino acid residues[5]. Both isoforms are structurally similar but not function-ally identical because ablation of the GSK3β isoform inmice resulted in embryonic lethality via hepatocyte apop-tosis. The inability of GSK3α to rescue the GSK3β-nullmice indicates that the degenerative liver phenotype arisesspecifically from the loss of the beta isoform. Although se-vere hepatocyte cell death could be due to β–catenin inhib-ition of NF-κB, increased amount of β–catenin in GSK3β(-/-) cells was not found [6]. Physical inhibitory interactionbetween β–catenin and NF-κB is likely a mechanism fortumor size progression mediated by β–catenin [7]. Alterna-tively, GSK3α knockout mice are viable but displayenhanced glucose and insulin sensitivity accompanied byreduced fat mass [8]. Mechanisms that regulate GSK3 ac-tivity are not yet fully understood. The precise control* Correspondence: baizabal@umich.mx1Centro Multidisciplinario de Estudios en Biotecnología, Facultad de MedicinaVeterinaria y Zootecnia, Universidad Michoacana de San Nicolás de Hidalgo,Morelia, Michoacán, Mexico3Centro Multidisciplinario de Estudios en Biotecnología, Facultad de MedicinaVeterinaria y Zootecnia, Universidad Michoacana de San Nicolás de Hidalgo,Km. 9.5 s/n Carretera Morelia-Zinapécuaro, La Palma, Tarímbaro, C.P. 58893,Morelia, Michoacán, MexicoFull list of author information is available at the end of the article© 2012 Cortés-Vieyra et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of theCreative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly cited.Cortés-Vieyra et al. Journal of Inflammation 2012, 9:23http://www.journal-inflammation.com/content/9/1/23appears to be achieved by a combination of intracellularlocalization, phosphorylation, and interactions with GSK3binding proteins [2]. In this regard, GSK3 has been trad-itionally considered a cytosolic protein; however, it is alsopresent in the nucleus and mitochondria, where it is highlyactive compared with the cytosolic form [9].The crystal structure of GSK3β has provided insight intoboth the regulation of its activation and its inhibition byphosphorylation [1]. GSK3 is activated by phosphorylationof Tyr216 (GSK3β) or Tyr279 (GSK3α) and it is inactivatedby phosphorylation of Ser9 (GSK3β) or Ser21 (GSK3α).Several protein kinases can phosphorylate Ser9 and Ser21,including the protein kinase B (PKB/Akt), protein kinase A(PKA), protein kinase C (PKC) and ribosomal protein 6kinase (S6K) [2,10]. The inactivation of GSK3β by phos-phorylation, carried out mainly by Akt, may result in theactivation of transcription factors such as AP-1 (Jun fam-ily), cAMP-response element binding protein (CREB),signal-transducer and activator of transcription 1-3(STAT1-3), β-catenin, and nuclear factor-kappaB (NF-κB)in response to bacterial infections [2,3] (Figure 1).NF-κB plays a critical role in the inflammatory responseand it has been traditionally used as an indicator of pro-inflammatory gene expression in cells exposed to bacterialinfections. When an inflammatory stimulus induces thephosphorylation of IκB by the IκB kinase (IKK) complex,the NF-κB heterodimer (p50/p65) is free to translocate tothe nucleus and activates pro-inflammatory gene expres-sion. GSK3β is important for the modulation of NF-κB be-cause p65 (RelA), p105 (NF-κB1) and B-cell lymphoma3-encoded protein (BCL-3) (a transcriptional co-activatorof NF-κB p50 homodimer) are phosphorylated in vitro bythis kinase [12,14]. GSK3β promotes a rapid NF-κB activa-tion wave by targeting the TNFα-/p65-dependent pathwayand limiting NF-κB activation in BCL-3-dependent path-ways [10] stabilizing and preventing p105 degradation inunstimulated cells [15]. However, GSK3β also catalyzes thephosphorylation of p105, which in turn activates thephosphorylation and degradation of IKK upon tumornecrosis factor alpha (TNF-α) treatment [15].Therefore, inbasal or stimulated cells GSK3β plays a double functionupon p105 [15]. Moreover, GSK3 plays distinct roles in theregulation of NF-κB, depending on the physiological stateof the cell. This enzyme promotes survival and stimulatesthe activity of NF-κB in cells treated with TNF-α or intumor cells in which the NF-κB pathway is constitutivelyactive. In contrast, in quiescent cells GSK3 suppresses theexpression of growth factor-inducible genes and inducesapoptosis or cell cycle arrest by inhibiting both the IKK-phosphorylation of IκBα and the nuclear translocation ofp50 and p65 subunits of NF-κB [16].In view of the contrasting effects that GSK3 plays as afunctional regulator of the cell activity, the followingsections of this review discuss our current knowledgeabout the importance of GSK3β as a regulator ofthe inflammatory process triggered by bacterial virulencefactors. Also, in the last section a brief overview on thenon-inflammatory phenomena induced by bacteria is pre-sented, which are correlated with the activity of GSK3.The inflammatory responseInflammation is the body’s primary response to infectionor injury and is critical for both innate and adaptive im-munity. Upon infection, a variety of cytokines, chemo-kines, lipid mediators and bioactive amines are secretedby resident tissue cells, primarily macrophages, dendriticcells, natural killer cells, and mast cells. These factorsimmediately trigger a local increase of blood flow, capil-lary permeability and recruitment of additional circulat-ing leukocytes via extravasation. This acute inflammatoryresponse is characterized by the arrival of neutrophils,monocytes that differentiate into macrophages at the siteof inflammation, and dendritic cells. This process is com-plex and involves many different signaling pathways.Most of our knowledge about pro-inflammatory signalingpathways has been obtained from studying the moleculesof signaling pathways that are initiated by the activationof tumor necrosis factor receptor (TNFR), interleukin 1receptor (IL1R), and Toll-like receptors (TLRs) [17]. Ac-tivation of TLRs by a variety of pathogen associated mo-lecular patterns (PAMPs) or virulence factors can inducethe expression of inflammatory cytokines and othermolecules that help to eliminate pathogens and instructpathogen-specific adaptive immune responses [18]. Cyto-kines, primarily derived from mononuclear phagocyticcells and other antigen-presenting cells (APCs), are ef-fective in promoting the cellular infiltrate and tissuedamage characteristic of inflammation. Monocytes arepotently triggered to produce cytokines through thestimulation of pattern recognition receptors (PRRs). Thepro-inflammatory cytokines predominantly produced bymonocytes include TNF, IL-1, IL-6, CXCL8 (IL-8) andother members of the chemokine family IL-12, IL-15, IL-18, IL-23 and IL-27 [19].During inflammation, leukocytes amplify the responsebut excessive or prolonged inflammation may causedamage to the host. In normal circumstances, the im-mune system has several mechanisms to resolve the in-flammatory responses that require the termination ofpro-inflammatory signaling pathways and clearance ofinflammatory cells, allowing the restoration of normaltissue function. Failure of these mechanisms may lead tochronic inflammation and disease [20]. In addition tocytokines that stimulate cytotoxic, cellular, humoral, andallergic inflammation, several cytokines have predomin-antly anti-inflammatory effects, including IL-1Ra, TGF-β,IL-10 and IL-35 [21]. Recently, a number of reports havedocumented that GSK3β activity is crucial to regulate theCortés-Vieyra et al. Journal of Inflammation 2012, 9:23 Page 2 of 9http://www.journal-inflammation.com/content/9/1/23inflammatory response either promoting or inhibitingthe process through the expression of pro- or anti-inflammatory cytokines.Inhibition of inflammation by inhibition of theGSK3β activitySeveral studies have demonstrated that inflammation isregulated by the TLR-dependent activation of PI3K-Aktsignaling pathway [3,22-26]. A breakthrough paper byMartin et al. [27] established that the PI3K-Akt-dependent inhibition of GSK3β activity in humanmonocytes, stimulated with lipopolysaccharide (LPS),differentially affected the nature and magnitude of theinflammatory response through the activation of TLR2.This in turn resulted in the production of the anti-inflammatory cytokine IL-10, while production of pro-inflammatory cytokines IL-1β, IL-6, TNF, IL-12 andIFN-α fell substantially. Inhibition of GSK3β negativelymodulated the inflammatory response because it differ-entially affected the nuclear activity of NF-κB (p65 sub-unit) and CREB through the interaction with the co-activator CREB-binding protein (CBP) [27]. In a recentFigure 1 GSK3β regulation of transcription factors activity is important for the modulation of inflammatory responses. Patternecognition receptors (PRRs) activation by pathogen-associated molecular patterns (PAMPs) or virulence factors recruits class IA ofphosphoinositide 3-kinases [PI3K IA (p85–p110)] to the membrane by direct interaction of the p85 subunit with the activated receptors or byinteraction with adaptor proteins associated with the receptors [3,11]. The activated p110 catalytic subunit converts phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3], providing docking sites for the signaling proteins3’-phosphoinositide-dependent kinase 1 (PDK1) and protein kinase B (PKB/Akt) that have pleckstrin homology domains [11]. Phosphatase andtensin homologue (PTEN) antagonizes the PI3K action by dephosphorylating [PtdIns(3,4,5)P3] [11]. Akt is phosphorylated and activated by PDK1and the mammalian target of rapamycin complexes 2 (mTORC2) at Thr308 and Ser473, respectively, and then is able to phosphorylate andinactivates glycogen synthase kinase-3 beta [GSK3β (S9)] [11]. GSK3β can be also phosphorylated and inactivated by protein kinase A/C (PKA/C)and by the mammalian target of rapamycin complexes 1 (mTORC1) through ribosomal protein 6 kinase (S6K) [3,10]. Inactivation of GSK3β resultsin the activation of transcription factors such as nuclear factor-κB (NF-κB), cAMP-response element binding protein (CREB), activator protein 1(AP-1), signal transducers and activators of transcription 1-3 (STAT1-3) and β-catenin that are involved in the regulation of the inflammatoryresponses [3,12,13]. GSK3β regulation on NF-κB is complex due to cell-, stimulus-, and promoter-selective interactions that might be stimulatoryor inhibitory [4].Cortés-Vieyra et al. Journal of Inflammation 2012, 9:23 Page 3 of 9http://www.journal-inflammation.com/content/9/1/23study carried out in monocytes stimulated with LPS, itwas established that the mammalian target of rapamycincomplex 1 (mTORC1) regulates the activity of GSK3βthrough the activation of S6K, affecting the inflamma-tory response by inactivation of GSK3β. Furthermore,the inhibition of GSK3β by mTORC1 affected the asso-ciation of NF-κB (p65 subunit) and CBP [10].GSK3β activity negatively regulated the level of theanti-inflammatory cytokine IL-1Ra while concurrentlyincreased the levels of IL1β in LPS-stimulated humanmonocytes. The PI3K-Akt-dependent inhibition of GSK3increased the production of IL-1Ra due to its ability tomodulate the activity of extracellular-signal-regulatedkinase 1/2 (ERK1/2) [28]. These results and the fact thatIL-1Ra counteracts the inflammatory properties of IL-1β[29] showed that in LPS-stimulated human monocytesthe inhibition of GSK3β increases the production ofanti-inflammatory cytokines and reduces the expressionof pro-inflammatory cytokines, confirming the modelproposed by Martin et al. [27], in which GSK3β in its ac-tive form acts as a positive regulator of inflammation.In a study with Mycobacterium bovis BCG as a Myco-bacterium model, it was demonstrated that GSK3β in-hibition through the PI3K-Akt signaling increased theproduction of IL-10 in primary human blood monocytes(PHBM) [30]. Among the cytokines induced by BCG inPHBM, IL-10 was the key factor suppressing the produc-tion of interferon-γ (IFN-γ) in response to mycobacterialinfection. Moreover, IL-10 expression induced by BCGwas able to suppress the IFN-γ-dependent expression ofHLA-DR, an inducible MHC class II molecule whoseprimary function is to present peptide antigens to theimmune system. These findings suggest a significant rolefor GSK3β in guarding against mycobacterial evasion ofhost immunity, via IL-10 expression.The PI3K-Akt signaling pathway activation followingthe nucleotide oligomerization domain 2 (Nod2) recog-nition of the agonist muramyldipeptide (MDP), a struc-ture from peptidoglycan (PGN), negatively regulates theNF-κB pathway and interleukin (IL)-8 expressionthrough inactivation of GSK3β. These results suggestthat the PI3K-Akt-GSK3β pathway may be involved inthe resolution of inflammatory responses induced byNod2 activation [31].Lipoteichoic acid (LTA) is a membrane-bound cell wallcomponent of Gram-positive bacteria and is believed tobe the equivalent of LPS of Gram-negative bacteria.Treatment of human gingival fibroblasts (HGFs) withLTA activated Akt which in turn inactivated GSK-3 andpromoted the accumulation of β-catenin, resulting inan increase of connexin43 expression [32]. Given thatthe interaction of β-catenin with NF-κB leads to a de-crease of the NF-κB ability to bind DNA and inducegene expression [7,33], it is likely that the accumulationof β-catenin in LTA-stimulated HGFs causes a negativeregulation of the NF-κB activity and that this gives riseto a decrease of the pro-inflammatory cytokines pro-duction [32]. It is also likely that GSK-3β inactivationmight be able to modulate the transcription of specificpro-inflammatory genes containing a T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) bindingsite in their promoter. In this regard, it was recentlydemonstrated that β-catenin induces pro- and anti-inflammatory responses simultaneously as a result ofdifferential gene expression carried out by Wnt/β-cate-nin signaling through a TCF/LEF consensus sequenceand NF-κB modulation in the context of liver cancer-related inflammation [34].Innate immunity and inflammatory responses playcentral roles in the pathophysiology of myocardial is-chaemia/reperfusion (I/R) injury and heart failure. Inthis context, it was observed that PGN administrationinduced cardio protection in hearts of mice subjected toischaemia, followed by reperfusion. Activation of thePI3K-Akt-GSK3β signaling pathway and reduction of theNF-κB nuclear translocation were the main factors re-sponsible for the protection [35]. Although one may as-sume that reduction of NF-κB nuclear translocationdecreased swelling, this waits further demonstration.Inhibition of inflammation by activation of GSK3βIn neonatal mouse cardiomyocytes and heart tissue cul-ture, LPS increased the activity of GSK3β and its inhib-ition with chemical and genetic inhibitors enhancedLPS-induced p65 phosphorylation at the residue Ser536and increased TNFα expression [36]. Furthermore, inline with GSK3β dephosphorylation at Ser9, Akt phos-phorylation at Thr308 was reduced in LPS-treated cardi-omyocytes and chemical inhibition of PI3K-Aktattenuated LPS-induced TNFα expression. These resultssuggest that PI3K-Akt-dependent inactivation of GSK3βplays an important function in LPS-induced TNF-αexpression.Induction of inflammation by inhibition of GSK3β activityThe production of pro- and anti-inflammatory cytokinesby activation of TLR2 and TLR4 in macrophages isdependent upon signaling events initiated by theadaptor molecules TIR-domain-containing adaptor pro-tein (TIRAP) and myeloid differentiation primary re-sponse gene 88 (MyD88) [13]. In contrast, inactivationof GSK3β by phosphorylation at Ser9 in macrophagesoccurred in the absence of MyD88 [32]. In this case,GSK3β activity was a critical component of the regula-tory mechanism that controlled the levels of IFNβ inTLR4-stimulated cells both in vitro and in vivo [37]. Inparticular, it was shown that inhibition of GSK3β activ-ity augmented the levels of IFNβ in LPS-stimulatedCortés-Vieyra et al. Journal of Inflammation 2012, 9:23 Page 4 of 9http://www.journal-inflammation.com/content/9/1/23macrophages whereas the ectopic expression of a consti-tutively active GSK3β mutant caused a reduction of theIFNβ production. Interestingly, inhibition of GSK3βcontrolled the cellular levels of the transcription factorc-Jun that turned out to be necessary for GSK3-mediated IFNβ production. The conclusion from theseresults is that GSK3β acts as a critical regulatory kinasethat modulated the MyD88-independent synthesis ofIFNβ and of MyD88-dependent production of pro- andanti-inflammatory cytokines, demonstrating the exist-ence of a cross-talk signaling network between thesetwo pathways with GSK3β as a central kinase [37].The intracellular infection of monocytes and macro-phages with Burkholderia cenocepacia, a Gram-negativebacterium associated with exacerbated inflammation[38], caused the activation of PI3K-Akt signaling that inturn inactivated GSK3β and enhanced NF-κB activity,with the subsequent production of pro-inflammatorycytokines such as, TNFα, IL-6 and IL-8. Interestingly,NF-κB activation did not require the activation of IKKor NF-κB p65 phosphorylation, indicating that the in-activation of GSK3β was the major mechanism by whichPI3K-Akt modulated the NF-κB activity without affect-ing B. cenocepacia uptake or survival [38].Induction of inflammation by activation of GSK3βA model in which IFN-γ specifically inhibits TLR2-dependent production of IL-10 in macrophages by in-creasing the activity of GSK3α/β, and decreasing the ex-pression and activity of CREB and AP-1 proteins hasbeen established [39]. Moreover, at the same time of IL-10 suppression, IFN-γ induced the expression of TNFα.In this study GSK3 and CREB/AP-1 were key players inthe signaling activated by the IFN-γ receptor and TLR2.Microglial inflammation caused by pathogenic S. aur-eus occurred through modulation of GSK3β activity thatpositively regulated the NF-κB-dependent production ofTNFα and nitric oxide (NO) [35]. GSK3β negativelyregulated IL-10 production, and this inhibition affectedthe protection against heat-inactivated S. aureus-inducedmicroglial inflammation [40]. These authors showed thatTNFα acted upstream of NO production and that inhib-ition of GSK3β blocked heat-inactivated S. aureus-induced NF-κB p65 nuclear translocation.In the study of the mechanisms by which GSK3β posi-tively modulates the inflammatory response in LPS-stimulated microglia, Wang et al. (2010) [41] showedthat inhibition of GSK3β activity by selective pharmaco-logical inhibitors or its gene silencing by small interfer-ing RNA suppressed TNFα production by blocking theNF-κB p65 transactivation activity through deacetylationof p65 at Lys310. In addition, these authors also demon-strated that inhibition of GSK3β blocked mixed lineagekinase 3 (MLK3) activity leading to a reduction of TNFαexpression.The role of GSK3β in modulating the β-catenin responsein colon inflammation caused by pathogenic SalmonellaTyphimurium was examined by using a streptomycin-pretreated mouse model [33]. S. Typhimurium induced anincrease in β-catenin phosphorylation by augmentingGSK3β activity, reducing total β-catenin expression andcompromising the physical cytoplasmic interaction be-tween β-catenin and NF-κB. IκBα, the well-establishednegative regulator of NF-κB, was degraded in a similarmanner as β-catenin after Salmonella infection. Followingβ-catenin and IκBα degradation, released NF-κB translo-cated to the nucleus and stimulated the production of thepro-inflammatory cytokines IL-6 and IL-8 [33]. The resultsof this study suggest a novel role for β-catenin as a negativeregulator of NF-κB activity in vivo. Altogether, these datasuggest that inhibition of GSK3β as well as β-catenin andIκBα stabilization provides important control points in theinflammatory cascade of colonic epithelial cells.The mechanisms by which IFN-γ synergizes with LPS toinduce iNOS/NO (important inductors in inflammatorycytokine production) biosynthesis in macrophages involveGSK3β-dependent inhibition of CREB activity and IL-10expression [42]. IFN-γ co-administration with LPS was alsoused to study the inflammatory responses modulated byGSK3 in mouse primary glia cultures [43]. In this case, ac-tive GSK3 decreased the expression of chemokine CXCL2/MIP-2 and increased the expression of pro-inflammatorymolecules CXCL1/KC, IL-12p40, CCL9/MIP-1γ, CCL2/MCP-1, P-Selectin and CCL5/RANTES. However andmost prominently, active GSK3 promoted IL-6 expressiondue to the cooperative actions of STAT3 and GSK3 duringneuro-inflammation. The production of IL-6 by glia waslargely blocked by inhibiting the activity of STAT3 orGSK3β, revealing the strong dependence of IL-6 produc-tion on these signaling molecules [43]. These data reflectthe cell’s ability to hyper-response to TLR-induced IFN-γproduction regulated by GSK3β, resulting in a synergismof the inflammatory response.The opposing functions of GSK3β in the inflammatoryresponse described in the text are summarized inTable 1.GSK3 regulation of non-inflammatory cellular processesactivated by bacterial componentsThe Helicobacter pylori virulence factor VacA is one ofthe most important toxins that contributes to the patho-genesis and severity of gastric injury in infected humans[44]. Although it is still controversial whether cross-talkexists between the PI3K-Akt and Wnt pathways [45], thework of Nakayama et al. [46] showed that VacA inducedtwo effects on β-catenin in gastric epithelial AZ-521cells. The first one was the activation and nuclearCortés-Vieyra et al. Journal of Inflammation 2012, 9:23 Page 5 of 9http://www.journal-inflammation.com/content/9/1/23Table 1 GSK3β modulation of the inflammatory response caused by bacterial stimuliBacterium or bacterialPAMPType of cell GSK3β Inhibition: + pSer9 NF-κB Inhibition #NF-kB Activation " Not tested -Pro or anti- inflammatorymolecules ExpressedPro or anti-inflammatorymolecules InhibitedRefs.GSK3β Activation:- pSer9 or + pTyr216LPS Human monocytes +pSer9 # IL-10 IL-1β, IL-6, TNF,IL-12, IFN-α[10,27]LPS Human monocytes +pSer9 - IL-1Ra IL-1β [28]Mycobacterium bovis Primary human monocytes +pSer9 - IL-10 IFN-γ [30]Muramyl dipeptide Human embryonic kidneyepithelial cells+pSer9 # - IL-8 [31]LPS Neonatal mouse cardiac cells # - TNF-α [36]LPS Mice macrophages + pSer9 - IFNβ - [37]Burkholderia cenocepacia Human monocytes andmouse macrophages+ pSer9 " TNF-α, IL-6, IL-8 - [38]Pam3Cysb and IFN-γ Human macrophages - pSer9 - TNFα IL-10 [39]Staphylococcus aureus Murine microglia + pTyr216 " TNF-α, NO IL10 [40]LPS Murine microglia A " TNF-α - [41]Salmonella typhimurium Mouse colonic epithelial cells - pSer9; + pTyr216 " TNF-α, IL-6 - [33]IFN-γ and LPS Murine macrophages + pTyr216 - iNOS, NO IL-10 [42]IFN-γ and LPS Mouse primary microgliaand astrocytesA - IL-6, CXCL1, IL-12p40,CCL9, CCL2/MCP-1,P- Selectin,CCL5CXCL2, MIP2 [43]A GSK3β phosphorylation at Ser9 or Tyr216 was not analyzed.b Synthetic PAMP.Cortés-Vieyraetal.JournalofInflammation2012,9:23Page6of9http://www.journal-inflammation.com/content/9/1/23accumulation of β-catenin following a short incubationwith VacA, a process dependent on an active PI3K-Aktpathway and an inactive GSK3β. The second effect wasthat prolonged incubation with VacA resulted in inactiva-tion of Akt and activation of GSK3β, which then down-regulated β-catenin activity. It was evident in this studythat Wnt signaling, modulated by PI3K-Akt-GSK3βplayed a role in the pathogenesis of H. pylori infection,including the development of gastric cancer [46].The lethal toxin (LeTx), produced by Bacillus anthra-cis, has been regarded as a key virulence factor in thepathogenesis of anthrax, causing immune paralysis, cellcycle arrest and cell death in host immune cells. Theseeffects could contribute to the survival and proliferationof B. anthracis within the host. LeTx is a binary A:Btoxin comprising protective antigen (PA) and lethal fac-tor (LF) [47]. PA is a molecular transporter that allowsreceptor-mediated entry and release of LF into the cyto-sol. LF is a zinc metalloprotease that cleaves and inacti-vates the N-terminal region of the mitogen-activatedprotein kinase (MAPK) kinases MEKs1-4 and 6-7,resulting in the inactivation of most of their downstreamsignaling substrates [47]. In non-dividing cells (humanperipheral blood mononuclear cells or mouse primaryperitoneal macrophages) brief exposure to LeTx inducedthe cleavage of MEKs by LF, generating cell cycle arrestin G0-G1 phase by rapid down-regulation of cyclin D1/D2 and checkpoint kinase 1 [47]. LF also prevented TNFproduction in response to LPS. However, it was observedthat recovery from the effects of LeTx can be facilitatedby activating the PI3K-Akt-GSK3β signaling-mediatedadaptive responses, indicating that modulation of thispathway can be beneficial against LeTx in cells depend-ing on basal MEK1 activity for proliferation [47].The inhibition of GSK3 via PI3K-Akt pathway has beenidentified in bacterial internalization processes in severalhost cells. For example, the invasion of HeLa cells bygroup B streptococcus (GBS) was associated with the acti-vation of the PI3K and Akt kinases and GSK3α/β phos-phoinibition [48]. One of the two type III secretionsystems (TTSSs) of Salmonella enterica serovar Typhimur-ium triggers bacterial internalization through activation ofPI3K-Akt [49]. Among the effectors proteins translocatedby this TTSS, the GTPase modulator SopE/E2 and thephosphoinositide phosphatase SigD are known to play keyroles in the process [49]. Using a reverse-phase proteinarray technology in HeLa, it was reported the SigD-dependent phosphorylation of Akt and its target GSK3β,demonstrating the importance of phosphoinhibition ofGSK3β during host cell signaling events through bacterialinfection [50]. Recently, the participation of PI3K-Akt-GSK3α/β pathway in Staphylococcus aureus internalizationby endothelial cells was demonstrated. Although the roleof the PI3K- Akt- dependent phosphorylation of GSK3α/βin the internalization of this bacterium was not determinedin this study, phosphorylation of GSK3β at Ser9 andGSK3α at Ser21 was clearly associated with the invasion ofS. aureus to the endothelial cells [51]. It is likely that in theinternalization of GBS and Salmonella enterica by HeLacells and S. aureus by endothelial cells, GSK3 functions byregulating the cytoskeletal rearrangement, as it wasobserved in macrophages RAW264.7 in which phosphoryl-ation of paxillin at Ser126 and 130 was mediated by anERK/GSK3 dual-kinase mechanism [52].ConclusionsThe experimental evidence accumulated so far indicatesthat GSK3β plays an essential role in the regulation ofthe inflammatory response during the interaction be-tween pathogenic bacteria and animal cells. The oppos-ing effects of GSK3β on the inflammation is dependentupon the bacterium or virulence factor (Mycobacteriumbovis, Burkholderia cenocepacia, Staphylococcus aureus,Salmonella typhimurium, LPS, MDP), the type of cell(epithelial cells, monocytes, cardiomyocytes, macro-phages, microglia or astrocytes and fibroblasts) andprobably on the physiological state of the cell [16]. Al-though activated NF-κB induces an inflammatory re-sponse, the active or inactive state of GSK3β modulatesthe activity of NF-κB, either promoting or inhibiting aninflammatory response.Apart from its fundamental regulatory role on the in-flammatory response, GSK3 is associated with bacterialinternalization [48,50,51] and other processes related tothe pathogenesis of the infection [46,47]. However, morestudies are needed to clarify the details about the mechan-isms that GSK3 employs to control the bacterialinternalization, the pathogenesis of infection and the ex-pression of genes with pro- or anti-inflammatory function.AbbreviationsAP-1: Activator protein 1; APCs: Antigen-presenting cells; BCL3: B-celllymphoma 3-encoded protein; CREB: cAMP-response element bindingprotein; ERK1/2: Extracellular-signal-regulated kinase 1/2; GSK3α/β: Glycogensynthase kinase-3 alpha/beta; HLA-DR: Major histocompatibility complex,MHC class II, cell surface receptor; LTA: Lipoteichoic acid; IFN-γ/β:Interferon-γ/β; IL1R: Interleukin 1 receptor; IKK: IκB kinase; MAPK:Mitogen-activated protein kinase; MLK3: Mixed lineage kinase 3;mTORC1/2: The mammalian target of rapamycin complexes 1/2;MDP: muramyldipeptide; MyD88: Myeloid differentiation primary responsegene 88; NF-κB: Nuclear factor-κB; NO: Nitric oxide; iNOS: inducible Nitricoxide synthase; Nod2: Nucleotide oligomerization domain 2;PAMPs: Pathogen associated molecular patterns; PDK1: 3’-phosphoinositide-dependent kinase 1; PKA/C: Protein kinase A/C; PKB: Protein kinase B; PI3KIA: Class IA of phosphoinositide 3-kinases; PTEN: Phosphatase and tensinhomologue; PRRs: Pattern recognition receptors; S6K: Ribosomal protein 6kinase; STAT1-3: Signal-transducer and activator of transcription 1-3; TCF/LEF: T-cell factor/lymphoid enhancer-binding factor; TIR: Toll/Interleukin-1receptor; TIRAP: TIR-domain-containing adaptor protein; TLRs: Toll-likereceptors; TRIF: TIR-domain-containing adapter-inducing interferon-β;TNFα: Tumor necrosis factor alpha; TNFR: Tumor necrosis factor receptor.Competing interestsThe authors declare that they have no competing interests.Cortés-Vieyra et al. Journal of Inflammation 2012, 9:23 Page 7 of 9http://www.journal-inflammation.com/content/9/1/23Authors’ contributionsRCV and VMBA conceived of the review, designed, and wrote themanuscript. ABP, JJVA, MCJ and BBF contributed to critical reading andcomments of the manuscript. All authors read and approved of the finalmanuscript.Acknowledgements and fundingThe authors thank Alejandro Huante-Mendoza and Octavio Silva-García fortheir valuable comments to the manuscript. Work on the correspondingauthor’s laboratory is supported by Coordinación de la InvestigaciónCientífica of the Universidad Michoacana de San Nicolás de Hidalgo andConsejo Nacional de Ciencia y Tecnología (CONACYT-México), grant number152518, and Programa Integral de Fortalecimiento Institucional(PIFI-2011-2012). VMB-A was a recipient of a sabbatical scholarship fromCONACYT-México, file 118602. B.B.F. is a CIHR Distinguished Investigator, aHoward Hughes Medical Institute International Research Scholar, and UBCPeter Wall Distinguished Professor. RC-V is receiving a doctoral scholarshipfrom CONACYT.Author details1Centro Multidisciplinario de Estudios en Biotecnología, Facultad de MedicinaVeterinaria y Zootecnia, Universidad Michoacana de San Nicolás de Hidalgo,Morelia, Michoacán, Mexico. 2Michael Smith Laboratories, The University ofBritish Columbia, Vancouver, BC V6T 1Z4, Canada. 3Centro Multidisciplinariode Estudios en Biotecnología, Facultad de Medicina Veterinaria y Zootecnia,Universidad Michoacana de San Nicolás de Hidalgo, Km. 9.5 s/n CarreteraMorelia-Zinapécuaro, La Palma, Tarímbaro, C.P. 58893, Morelia, Michoacán,Mexico.Received: 12 January 2012 Accepted: 22 May 2012Published: 12 June 2012References1. Doble BW, Woodgett JR: GSK-3, tricks of the trade for a multi-taskingkinase. J Cell Sci 2003, 116:1175–1186.2. 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Journal of Inflammation 2012 9:23.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitCortés-Vieyra et al. Journal of Inflammation 2012, 9:23 Page 9 of 9http://www.journal-inflammation.com/content/9/1/23

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