Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells

Ohtani, Misato; Nagai, Shigenori; Kondo, Shuhei; Mizuno, Shinta; Nakamura, Kozue; Tanabe, M.; Takeuchi, Tsutomu; Matsuda, Shinji; Koyasu, Shigeo

doi:10.1182/blood-2008-02-137430

Cited by 224 publications

(276 citation statements)

References 48 publications

(72 reference statements)

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“…MTORC2 also improves glycolytic metabolism by activating the AKT [121], [122]. Thus mTOR negatively regulates the GSK-3 activity to limit production of IL-12 [114], [117]. Our data is consistent with mTORC1 acting as negative regulator of IL-12 and facilitator of production of IL-10 after exposure to microbial agents.…”

Section: B Cytoscapesupporting

confidence: 86%

Untitled

2017

RJLBPCS

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ABSTRACT:One of the many challenges of bioinformatics, now a day; is the integration of biological data.The establishment of large quantities of data concerning the differentially expressed genes during infection with an intracellular pathogen requires the implementation of integration strategies to gather all the data and therefore a better understanding of the functioning of the Intracellular infection. This work aims to exploit the bioinformatics approach, to provide a new interpretation of the data available in the literature as well as databases on the effect of intracellular infection, cases of the Leishmania parasite, on the host. A total of 30 genes expressed differently from a Leishmania parasite infection were used for functional analysis using the bioinformatics tool. The latter provides rapid assessment of signaling and metabolic pathways, molecular networks and biological processes that are more significantly disrupted in a data set of interest. Bioinformatics analysis revealed that apoptosis, cytokine production, and signaling were altered following infection with the Leishmania parasite. The genes of IL-10, IL-4, IL-6, SOD1, EIF2AK2, NF-kB and PI3K/akt were most activated after Infection by the Leishmania parasite. The results suggest that the Leishmania parasite reverses immune and inflammatory responses, meaning the ability to induce programmed cell death and microbicidal functions of macrophages such as inhibition of nitric oxide (NO), And the functions of the inducible cytokines of macrophages. Analyzing and interpreting data using the bioinformatics approach helps to unlock knowledge buried in experimental data by quickly identifying links, mechanisms, functions and main pathways to move beyond Statistical analysis to new biological analyzes.

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Section: B Cytoscapesupporting

confidence: 86%

Untitled

2017

RJLBPCS

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“…S3A), consistent with previous reports. 26,28 The exquisite sensitivity of IL-10 production to mTOR signaling was confirmed over a wider dose range by Meso Scale Discovery (MSD), revealing the EC 50 of the IL-10 inhibitory effect conferred by vistusertib was between ∼30-100nM (Fig. S3B).…”

Section: Resultsmentioning

confidence: 90%

“…This finding is in agreement with several reports showing that mTORC1 inhibition or mTOR ablation can enhance proinflammatory phenotypes in DCs. 25,26,29 Vistusertib has previously been shown to limit IL-10 production by tumour cells themselves in diffuse large B-cell lymphoma (DLBCL) cell lines, 43 suggesting this mechanism may extend beyond immune cells to more broadly impact the tumour microenvironment in some contexts. The IL-10:IL-12 axis has been recently identified as an important indicator of chemotherapeutic responses, with IL-10 shown to limit subsequent intratumoral cytotoxic T-cell activity.…”

Section: Discussionmentioning

confidence: 99%

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

et al. 2018

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ABSTRACTmTOR inhibition can promote or inhibit immune responses in a context dependent manner, but whether this will represent a net benefit or be contraindicated in the context of immunooncology therapies is less understood. Here, we report that the mTORC1/2 dual kinase inhibitor vistusertib (AZD2014) potentiates anti-tumour immunity in combination with anti-CTLA-4 (αCTLA-4), αPD-1 or αPD-L1 immune checkpoint blockade. Combination of vistusertib and immune checkpoint blocking antibodies led to tumour growth inhibition and improved survival of MC-38 or CT-26 pre-clinical syngeneic tumour models, whereas monotherapies were less effective. Underlying these combinatorial effects, vistusertib/immune checkpoint combinations reduced the occurrence of exhausted phenotype tumour infiltrating lymphocytes (TILs), whilst increasing frequencies of activated Th1 polarized T-cells in tumours. Vistusertib alone was shown to promote a Th1 polarizing proinflammatory cytokine profile by innate primary immune cells. Moreover, vistusertib directly enhanced activation of effector T-cell and survival, an effect that was critically dependent on inhibitor dose. Therefore, these data highlight direct, tumour-relevant immune potentiating benefits of mTOR inhibition that complement immune checkpoint blockade. Together, these data provide a clear rationale to investigate such combinations in the clinic.

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“…Moreover, the 723 dramatic effect of LdGSK-3s inhibitors on Leishmania, especially the intramacrophage amastigote 724 stage, suggests that LdGSK-3s has potential as a drug target in these parasites. Future work would 725 be required to develop parasite-selective inhibitors that do not target host GSK-3 since its inhibition 726 may affect the balance between Th1 and Th2 rsponses (Ohtani et al, 2008). In addition, RNAi 727 studies of TbruGSK-3 lead to similar cellular phenotypes, such as growth inhibition and altered 728 parasite morphology (Ojo et al, 2008), to that caused by GSK-3 inhibitors in Leishmania.…”

Section: G2/m 548mentioning

confidence: 99%

6-Br-5methylindirubin-3′oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: Exploitation of GSK-3 for treating leishmaniasis

Xingi

Smirlis

Myrianthopoulos

et al. 2009

International Journal for Parasitology

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Indirubins known to target mammalian cyclin-dependent kinases (CDKs) and glycogen synthase kinase (GSK-3) were tested for their antileishmanial activity. 6-Br-indirubin-3'-oxime (6-BIO), 6-Br-indirubin-3'acetoxime and 6-Br-5methylindirubin-3'oxime (5-Me-6-BIO) were the most potent inhibitors of L. donovani promastigote and amastigote growth (IC50 values ≤ 1.2 μM). Since the 6-Br substitution on the indirubin backbone greatly enhances the selectivity for mammalian GSK-3 over CDKs, we identified the leishmanial GSK-3 homologues, a short (LdGSK-3s) and a long one, focusing on LdGSK-3s which is closer to human GSK-3β for further studies. Kinase assays showed that 5-Me-6-BIO inhibited LdGSK-3s more potently than CRK3 (the CDK1 homologue in Leishmania), while 6-BIO was more selective for CRK3. Promastigotes treated with 5-Me-6-BIO accumulated in the S and G2/M cell-cycle phases and underwent apoptosis-like death.Interestingly, these phenotypes were completely reversed in parasites over-expressing LdGSK-3s.This finding strongly supports that LdGSK-3s is a) the intracellular target of 5-Me-6-BIO and b) involved in cell-cycle control and in pathways leading to apoptosis-like death. 6-BIO treatment induced a G2/M arrest, consistent with inhibition of CRK3, and apoptosis-like death. These effects were partially reversed in parasites over-expressing suggesting that in vivo 6-BIO may also target LdGSK-3s. Molecular docking of 5-Me-6-BIO in CRK3 and 6-BIO in human and LdGSK-3s active sites predict the existence of functional/structural differences that are sufficient to explain the observed difference in their affinity. In conclusion, LdGSK-3s is validated as a potential drug target in Leishmania and could be exploited for the development of selective indirubin-based leishmanicidals. AUTHOR AGREEMENT FORMManuscript title: "5-Me-6-BIO targeting the leishmanial GSK-3 short form affects cell-cycle progression and induces apoptosis-like death: exploitation of GSK-3 for treating leishmaniasis" Authors: Evangelia Xingi, Despina Smirlis , Vassilios Myrianthopoulos , Prokopios Magiatis, Karen M. Grant, Laurent Meijer, Emmanuel Mikros, Alexios-Leandros Skaltsounis and Ketty Soteriadou We, the undersigned, acknowledge that we have read the above manuscript and accept responsibility for its contents. We confirm this manuscript has not been published previously and if accepted in the International Journal for Parasitology will not be published elsewhere without the approval of the Editor-in-Chief. We also confirm there are no financial or other relationships that might lead to a conflict of interest.[If a financial or other relationship exists that might lead to a conflict of interest, please provide that information here.][If this letter is being submitted at revision and if there have been any changes in authors added to/deleted from the paper or if the order of author citation has changed since the original submission, please include a statement acknowledging those changes, before each author (including authors deleted fro...

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Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells

Cited by 224 publications

References 48 publications

Untitled

Untitled

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

6-Br-5methylindirubin-3′oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: Exploitation of GSK-3 for treating leishmaniasis

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