Identification of a Role for the PI3K/AKT/mTOR Signaling Pathway in Innate Immune Cells

Xie, Songbo; Chen, Miao; Yan, Bing; He, Xianfei; Chen, Xiwen; Li, Dengwen

doi:10.1371/journal.pone.0094496

Cited by 133 publications

(108 citation statements)

References 42 publications

(39 reference statements)

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“…The mTOR signaling pathway provides a direct metabolic link between immune cells and microenvironment, but the immunologic regulation due to mTOR inhibition is complex and cell type dependent (24,25). In monocytes and macrophages, mTORC1 inhibitors such as rapamycin and everolimus appear to evoke pro-and antiinflammatory cytokine production (25,41), macrophage polarization (42) and autophage (43). Targeting mTOR signaling pathway via FRs may be a useful approach to curtail autoimmune and other diseases caused or worsened by activated macrophages.…”

Section: Discussionmentioning

confidence: 99%

Antiinflammatory Activity of a Novel Folic Acid Targeted Conjugate of the mTOR Inhibitor Everolimus

Parker

Kleindl

et al. 2015

Mol Med

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Section: Discussionmentioning

confidence: 99%

Antiinflammatory Activity of a Novel Folic Acid Targeted Conjugate of the mTOR Inhibitor Everolimus

Parker

Kleindl

et al. 2015

Mol Med

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“…The mechanism of infection with the new classes of PI3K-AKTmTOR inhibitors is not fully understood, however, there is evidence that the PI3K-AKT-mTOR signaling pathway regulates the production of cytokines in innate immune cells (15). Furthermore, T cells are dependent on this signaling pathway for their differentiation, activation, maintenance, and trafficking (32)(33)(34).…”

Section: Predictive Markers Of Infection With Pi3k-akt-mtor Inhibitorsmentioning

confidence: 99%

“…As well as its role in normal cell growth, regulation of blood glucose homeostasis and lipid metabolism (10)(11)(12)(13)(14), the PI3K-AKT-mTOR pathway plays an important role in regulating the immune system and cytokines production by immune cells (15). Emerging data indicate that the inhibition of PI3K signaling reduces the generation and suppresses the secretion of proinflammatory cytokines and leads to an attenuated immune response (15)(16)(17)(18). It is known that mTOR inhibitors regulate the immune function and are licensed for use in renal transplantation (19,20).…”

Section: Introductionmentioning

confidence: 99%

Higher Risk of Infections with PI3K–AKT–mTOR Pathway Inhibitors in Patients with Advanced Solid Tumors on Phase I Clinical Trials

Rafii

Roda

Geuna

et al. 2015

Clinical Cancer Research

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Novel antitumor therapies against the PI3K-AKT-mTOR pathway are increasingly used to treat cancer, either as single agents or in combination with chemotherapy or other targeted therapies. Although these agents are not known to be myelosuppressive, an increased risk of infection has been reported with rapamycin analogs. However, the risk of infection with new inhibitors of this pathway such as PI3K, AKT, mTORC 1/2 or multi-kinase inhibitors is unknown. Methods In this retrospective case-control study, we determined the incidence of infection in a group of 432 patients who were treated on 15 phase I clinical trials involving PI3K-AKT-mTOR pathway inhibitors (cases) vs a group of 100 patients on 10 phase I clinical trials of single agent non-PI3K-AKT-mTOR pathway inhibitors (controls) which did not involve conventional cytotoxic agents. We also collected data from 42 patients who were treated with phase I trials of combinations of PI3K-AKT-mTOR inhibitors and MEK inhibitors and 24 patients with combinations of PI3K-AKT-mTOR inhibitors and cytotoxic chemotherapies. Results The incidence of all grade infection was significantly higher with all single agent PI3K-AKT-mTOR inhibitors compared to the control group (27% vs 8% respectively, OR: 4.26, 95% CI: 1.9-9.1, p=0.0001). The incidence of grade 3 and 4 infection was also significantly higher with PI3K-AKT-mTOR inhibitors compared to the control group (10.3% vs 3%, OR: 3.74, 95% CI: 1.1-12.4, p=0.02). Also the combination of PI3K-AKT-mTOR inhibitors and chemotherapy was associated with a significantly higher incidence of all grade (OR: 4.79, 95% CI: 2.0-11.2, p=0.0001) and high grade (OR: 2.87, 95% CI: 1.0-7.6, p=0.03) infection when compared with single agent PI3K-AKT-mTOR inhibitors. Conclusion Inhibitors of the PI3K-AKT-mTOR pathway can be associated with a higher risk of infection. Combinations of PI3K-AKT-mTOR inhibitors and cytotoxic chemotherapy significantly increase the risk of infection. This should be taken into consideration during the design and conduct of trials involving PI3K-AKT-mTOR pathway inhibitors, particularly when combined with chemotherapy or myelosuppressive agents.

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“…The PI3K/Akt/p70S6K pathway has been shown to regulate a number of cellular processes, including gene expression and inflammation (Xie et al, 2014). To investigate the involvement of PI3K/Akt and p70S6K in the modulation of SREBP-1c and NLRP3 expression by HGPg infection, HGFs were incubated with specific inhibitors for PI3K/Akt (LY294002) and p70S6K (rapamycin) for 1 h before and during infection with HGPg.…”

Section: Resultsmentioning

confidence: 99%

Sterol Regulatory Element-Binding Protein-1c Regulates Inflammasome Activation in Gingival Fibroblasts Infected with High-Glucose-Treated Porphyromonas gingivalis

Kuo

Chang

Chen

et al. 2016

Front. Cell. Infect. Microbiol.

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Background: Porphyromonas gingivalis is a major bacterial species implicated in the progression of periodontal disease, which is recognized as a common complication of diabetes. The interleukin (IL)-1β, processed by the NLR family pyrin domain containing 3 (NLRP3) inflammasome, has been identified as a target for pathogenic infection of the inflammatory response. However, the effect of P. gingivalis in a high-glucose situation in the modulation of inflammasome activation in human gingival fibroblasts (HGFs) is not well-understood.Methods: P. gingivalis strain CCUG25226 was used to study the mechanisms underlying the regulation of HGF NLRP3 expression by the infection of high-glucose-treated P. gingivalis (HGPg).Results: HGF infection with HGPg increases the expression of IL-1β and NLRP3. We further demonstrated that the upregulation of sterol regulatory element-binding protein (SREBP)-1c by activation of the Akt and p70S6K pathways is critical for HGPg-induced NLRP3 expression. We showed that the inhibition of Janus kinase 2 (JAK2) blocks the Akt- and p70S6K-mediated SREBP-1c, NLRP3, and IL-1β expression. The effect of HGPg on HGF signaling and NLRP3 expression is mediated by β1 integrin. In addition, gingival tissues from diabetic patients with periodontal disease exhibited higher NLRP3 and SREBP-1c expression.Conclusions: Our findings identify the molecular pathways underlying HGPg-dependent NLRP3 inflammasome expression in HGFs, providing insight into the effect of P. gingivalis invasion in HGFs.

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Identification of a Role for the PI3K/AKT/mTOR Signaling Pathway in Innate Immune Cells

Cited by 133 publications

References 42 publications

Antiinflammatory Activity of a Novel Folic Acid Targeted Conjugate of the mTOR Inhibitor Everolimus

Antiinflammatory Activity of a Novel Folic Acid Targeted Conjugate of the mTOR Inhibitor Everolimus

Higher Risk of Infections with PI3K–AKT–mTOR Pathway Inhibitors in Patients with Advanced Solid Tumors on Phase I Clinical Trials

Sterol Regulatory Element-Binding Protein-1c Regulates Inflammasome Activation in Gingival Fibroblasts Infected with High-Glucose-Treated Porphyromonas gingivalis

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