PI3Kδ and PI3Kγ: partners in crime in inflammation in rheumatoid arthritis and beyond?

Rommel, Christian; Camps, Montserrat; Ji, Hong

doi:10.1038/nri2036

Cited by 386 publications

(365 citation statements)

References 125 publications

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“…The results confirmed that 9AA treatment results in downregulation of p110g levels. In addition, whereas p110g expression Small molecule targeting AKT/mTOR, PI3K, NF-jB and p53 pathways C Guo et al was previously shown to be limited to cells of hematological origin (Camps et al, 2005;Rommel et al, 2007), we found that p110g is expressed in tumor cell lines of various origins, including RCC, fibrosarcoma (HT1080), colon carcinoma (HCT116). We tested different 9AA doses and lengths of treatment and observed downregulation of p110g expression as early as 4-8 h after treatment with at least 5 mM 9AA (Figure 1 and data not shown).…”

Section: P110g Expression Is Decreased In Tumor Cells Treated With 9aamentioning

confidence: 57%

9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-κB and p53 pathways

et al. 2009

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Acquisition of a transformed phenotype involves deregulation of several signal transduction pathways contributing to unconstrained cell growth. Understanding the interplay of different cancer-related signaling pathways is important for development of efficacious multitargeted anticancer drugs. The small molecule 9-aminoacridine (9AA) and its derivative, the antimalaria drug quinacrine, have selective toxicity for tumor cells and can simultaneously suppress nuclear factor-jB (NF-jB) and activate p53 signaling. To investigate the mechanism underlying these drug activities, we used a combination of twodimensional protein separation by gel electrophoresis and mass spectrometry to identify proteins whose expression is altered in tumor cells by 9AA treatment. We found that 9AA treatment results in selective downregulation of a specific catalytic subunit of the phosphoinositide 3-kinase (PI3K) family, p110c. Further exploration of this observation demonstrated that the mechanism of action of 9AA involves inhibition of the prosurvival AKT/ mammalian target of rapamycin (mTOR) pathway that lies downstream of PI3K. p110c translation appears to be regulated by mTOR and feeds back to further modulate mTOR and AKT, thereby impacting the p53 and NF-jB pathways as well. These results reveal functional interplay among the PI3K/AKT/mTOR, p53 and NF-jB pathways that are frequently deregulated in cancer and suggest that their simultaneous targeting by a single small molecule such as 9AA could result in efficacious and selective killing of transformed cells.

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Section: P110g Expression Is Decreased In Tumor Cells Treated With 9aamentioning

confidence: 57%

9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-κB and p53 pathways

et al. 2009

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“…In the current study, a 2 ARmediated signaling induced PI3K activation and rapid endocytosis in DCs, and blocking PI3K activation inhibited NAmediated endocytosis. PI3Ks are divided into class I, class II, and class III, based on their structural similarities (31,32). Class I PI3Ks control many cellular functions, including growth, proliferation, survival, adhesion, and migration.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Dendritic Cell Antigen Uptake via α2 Adrenoceptor-Mediated PI3K Activation Following Brief Exposure to Noradrenaline

Yanagawa

Matsumoto

Togashi

2010

The Journal of Immunology

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Although noradrenaline (NA), a stress-associated neurotransmitter, seems to affect the immune system, the precise mechanisms underlying NA-mediated immunoregulation are not fully understood. We examined the effect of NA on Ag uptake (endocytosis) by dendritic cells (DCs) using murine bone marrow-derived DCs and fluorescence-labeled endocytic tracers (dextran and OVA). Ag uptake by DCs notably increased following a very brief treatment (3 min) with NA. NA-induced endocytosis was completely blocked by treatment with α2-adrenoceptor antagonist yohimbine. Neither α1-adrenoceptor antagonist prazosin nor β-adrenoceptor antagonist propranolol affected NA-induced endocytosis by DCs. A selective α2-adrenoceptor agonist, azepexole (B-HT 933), also significantly increased endocytosis by DCs. Thus, the α2-adrenoceptor seems to be responsible for NA-induced DC endocytosis. In parallel, NA markedly activated intracellular signaling pathways of PI3K and ERK1/2 in DCs. NA-mediated activation of these pathways was completely inhibited by yohimbine treatment. Blocking PI3K activation significantly reduced NA-induced endocytosis by DCs. Based on these results, NA rapidly enhances Ag capture by DCs via α2 adrenoceptor-mediated PI3K activation, which may be associated with immune enhancement following acute stress.

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“…It was recently demonstrated that both airway eosinophilia and remodeling were reduced in phosphoinositide 3 kinase γ (PI3Kγ)-deficient mice challenged with OVA (27). Because PI3Kγ is known to be expressed particularly in leukocytes (28) and is known to be activated by G protein-coupled chemokine receptors to induce leukocyte migration (28), it was suggested that chemokines such as eotaxin play key roles in not only airway eosinophilia but also airway remodeling. Whether the infiltrated eosinophils are involved in remodeling should be further examined under the condition in which eosinophilia completely disappeared.…”

Section: Effects Of Anti-il-5 Mab On the Development Of Airway Remodementioning

confidence: 99%

Complete Dependence on CD4+ Cells in Late Asthmatic Response, but Limited Contribution of the Cells to Airway Remodeling in Sensitized Mice

Nabe¹,

Morishita²,

Matsuya³

et al. 2011

J Pharmacol Sci

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Abstract. It is known that the late asthmatic response (LAR), a characteristic feature of asthma, is closely associated with CD4 + Th2 cell-mediated allergic inflammation. Airway remodeling is also a pathogenesis of asthma, but literature reporting roles of CD4 + cells in the remodeling is controversial. There has been no study that simultaneously assessed the roles of CD4 + cells in both LAR and airway remodeling. Sensitized mice were intratracheally challenged with ovalbumin 4 times. Treatment with an anti-CD4 monoclonal antibody (mAb) before the 1st challenge almost completely abolished increase in CD4 + cells in the tissues after the 4th challenge. The late phase increase in airway resistance after the 4th challenge was also completely inhibited by anti-CD4 mAb. Parameters of airway remodeling, subepithelial fibrosis and epithelial thickening were attenuated by treatment, whereas the inhibition was only 30% -40%. Bronchial smooth muscle thickening was not affected. Because interleukin (IL)-5 production as well as eosinophilia was effectively suppressed by anti-CD4 mAb, the effect of anti-IL-5 mAb was also examined, resulting in no inhibition of airway remodeling. Collectively, although the LAR was completely dependent on CD4 + cell activation, airway remodeling was only partially dependent on the cell.

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PI3Kδ and PI3Kγ: partners in crime in inflammation in rheumatoid arthritis and beyond?

Cited by 386 publications

References 125 publications

9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-κB and p53 pathways

9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-κB and p53 pathways

Enhanced Dendritic Cell Antigen Uptake via α2 Adrenoceptor-Mediated PI3K Activation Following Brief Exposure to Noradrenaline

Complete Dependence on CD4+ Cells in Late Asthmatic Response, but Limited Contribution of the Cells to Airway Remodeling in Sensitized Mice

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