A preferential p110α/γ PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-κB-dependent manner

Dagia, Nilesh M.; Agarwal, Gautam; Kamath, Divya; Chetrapal-Kunwar, Anshu; Gupte, Ravindra D.; Jadhav, Mahesh; Dadarkar, Shruta S.; Trivedi, Jacqueline; Kulkarni-Almeida, Asha; Kharas, Firuza; Fonseca, Lyle C.; Kumar, Sanjay; Bhonde, Mandar

doi:10.1152/ajpcell.00461.2009

Cited by 45 publications

(36 citation statements)

References 56 publications

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“…Cytokine Expression-In addition to the role played by STAT1 and STAT3, we investigated whether NF-B, a transcription factor commonly associated with cytokine regulation (17)(18)(19)(20)(21), was induced by IL-27 in monocytic cells. THP-1 cells were treated with IL-27 for times ranging from 5-120 min, followed by Western blot analysis for phosphorylated NF-B p50 subunit (p-NF-B p50) (Fig.…”

Section: Inhibition Of Nf-b Dna Binding Activity Blocks Il-27-inducedmentioning

confidence: 99%

Interleukin-27 Induces a STAT1/3- and NF-κB-dependent Proinflammatory Cytokine Profile in Human Monocytes

Guzzo¹,

Mat²,

Gee

2010

Journal of Biological Chemistry

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IL-27 is a heterodimeric cytokine bridging innate and adaptive immunity by playing a role in the activation of naive T cells and in development of Th1 cells. Additionally, recent evidence supports a role for IL-27 in the activation of monocytic cells. Both pro-inflammatory and anti-inflammatory activities have been attributed to IL-27; however, the role played by IL-27 in the activation of human monocytic cells in terms of cytokine production has not been well described. Our results show that IL-27 is a strong inducer of proinflammatory cytokine and chemokine expression, including enhancement of IL-6, IP-10, MIP-1␣, MIP-1␤, and TNF-␣ expression in human primary monocytes. Furthermore, we observed that IL-27-induced cytokine and chemokine production was mediated by STAT1, STAT3, and NF-B activation. Understanding how IL-27 exerts its effects on monocytic cells will identify important molecular mechanisms in the regulation of immune responses, particularly in the modulation of monocyte activation.

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Section: Inhibition Of Nf-b Dna Binding Activity Blocks Il-27-inducedmentioning

confidence: 99%

Interleukin-27 Induces a STAT1/3- and NF-κB-dependent Proinflammatory Cytokine Profile in Human Monocytes

Guzzo¹,

Mat²,

Gee

2010

Journal of Biological Chemistry

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“…The PIK-75 treatment was well tolerated, and normal numbers and percentages of the main lymphocyte populations were observed 20 days after termination. Previous results have also shown that PIK-75 inhibits secretion of inflammatory cytokines in cells from patients with active rheumatoid arthritis (14). This suggested that PIK-75 might be useful as a therapeutic agent in arthritis.…”

Section: Discussionmentioning

confidence: 76%

“…In contrast, using PIK-75, we have observed strong effects on activated or resting T cells at ten-fold lower concentrations (::::0.1~M), and clear effects on cytokine secretion or proliferation using concentrations as low as 0.01~M PIK-75. These differences among inhibitors are not likely due to differences in their p 11 Oa IC so [0.006 and 0.032 mM, respectively, for PIK-75 and A66 (19)], and seem specific for lymphocytes, as an IC so 2:20 mM for PIK-75 toxicity in monocytes and synovia have been reported (14). Inhibition of other Class I PI3-K isoforms might be involved as the IC so of PIK-75 is relatively low (0.080, 0.164 and 0.033 mM for p110~, p1100 and pi lOy, respectively) (19).…”

Section: Discussionmentioning

confidence: 90%

“…Taking into account previous data showing that administration of PIK-75 alleviates dextran sulfate-induced colitis (14), and in view of its effect on lymphocyte subpopulations and cytokines involved in EAE (33), we analyzed the effect of PIK-75 administration on MaG-induced EAE. Administration ofPIK-75 during the effector phase of EAE inhibited the clinical symptoms of treated mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, previous data show that oral administration ofPIK-75 significantly inhibits IL-6 secretion in monocytes and ameliorates dextran sulfate sodium (DSS)-induced colitis, an experimental model of inflammatory bowel disease (14). Thus, we sought to determine the effect ofPIK-75 in a model of EAE that is dependent on CD4+ T cells.…”

Section: Effect Of Pik-75 In Experimental Autoimmune Encephalitismentioning

confidence: 99%

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Suppression of CD4⁺T Lymphocyte Activationin Vitroand Experimental Encephalomyelitisin Vivoby the Phosphatidyl Inositol 3-Kinase Inhibitor PIK-75

Acosta

Montes-Casado

Aragoneses-Fenoll

et al. 2014

Int J Immunopathol Pharmacol

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Class IA phosphatidyl inositol-3 kinases (PI3-K) are important targets in cancer therapy and are essential to immune responses, particularly through costimulation by CD28 and ICOS. Thus, small PI3-K inhibitors are likely candidates to immune intervention. PIK-75 is an efficient inhibitor of the PI3-K p110α catalytic subunits that suppresses tumor growth, and its effects on immune and autoimmune responses should be studied. Here, we describe the effect of PIK-75 on different immune parameters in vitro and in vivo. PIK-75 at concentrations commonly used in vitro (≥0.1 μM) inhibited T and B cell activation by Concanavalin A and LPS, respectively, and survival of non-stimulated spleen cells. In naive CD4+ T lymphocytes, PIK-75 induced apoptosis of resting or activated cells that was prevented by caspase inhibitors. At low nanomolar concentrations (≤10 nM), PIK-75 inhibited naive CD4+ T cell proliferation, and IL-2 and IFN-γ production induced by anti-CD3 plus anti-CD28. In activated CD4+ T blasts costimulated by ICOS, PIK-75 (≤10 nM) inhibited IFN-γ, IL-17A, or IL-21 secretion. Furthermore, PIK-75 (20 mg/kg p.o.) suppressed clinical symptoms in ongoing experimental autoimmune encephalomyelitis (EAE) and inhibited MOG-specific responses in vitro. Thus, PIK-75 is an efficient suppressor of EAE, modulating lymphocyte function and survival.

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miR‐124a inhibits the proliferation and inflammation in rheumatoid arthritis fibroblast‐like synoviocytes via targeting PIK3/NF‐κB pathway

Yang

Zhou

et al. 2019

Cell Biochemistry & Function

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Abnormal hyperplasia of fibroblast-like synoviocytes (FLS) leads to the progression of rheumatoid arthritis (RA). This study aimed to investigate the role of miR-124a in the pathogenesis of RA. The viability and cell cycle of FLS in rheumatoid arthritis (RAFLS) were evaluated by Cell Counting Kit 8 and flow cytometry assay. The expression of PIK3CA, Akt, and NF-κB in RAFLS was examined by real-time PCR and Western blot analysis. The production of tumour necrosis factor (TNF)-α and interleukin (IL)-6 was detected by ELISA. The joint swelling and inflammation in collagen-induced arthritis (CIA) mice were examined by histological and immunohistochemical analysis. We found that miR-124a suppressed the viability and proliferation of RAFLS and increased the percentage of cells in the G1 phase. miR-124a suppressed PIK3CA 3'UTR luciferase reporter activity and decreased the expression of PIK3CA at mRNA and protein levels. Furthermore, miR-124a inhibited the expression of the key components of the PIK3/Akt/NF-κB signal pathway and inhibited the expression of pro-inflammatory factors TNF-α and IL-6. Local overexpression of miR-124a in the joints of CIA mice inhibited inflammation and promoted apoptosis in FLS by decreasing PIK3CA expression. In conclusion, miR-124a inhibits the proliferation and inflammation in RAFLS via targeting PIK3/NF-κB pathway. miR-124a is a promising therapeutic target for RA.

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A preferential p110α/γ PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-κB-dependent manner

Abstract: MR.A preferential p110␣/␥ PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-Bdependent manner.

Cited by 45 publications

References 56 publications

Interleukin-27 Induces a STAT1/3- and NF-κB-dependent Proinflammatory Cytokine Profile in Human Monocytes

Interleukin-27 Induces a STAT1/3- and NF-κB-dependent Proinflammatory Cytokine Profile in Human Monocytes

Suppression of CD4⁺T Lymphocyte Activationin Vitroand Experimental Encephalomyelitisin Vivoby the Phosphatidyl Inositol 3-Kinase Inhibitor PIK-75

miR‐124a inhibits the proliferation and inflammation in rheumatoid arthritis fibroblast‐like synoviocytes via targeting PIK3/NF‐κB pathway

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A preferential p110α/γ PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-κB-dependent manner

Abstract: MR.A preferential p110␣/␥ PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-Bdependent manner.

Cited by 45 publications

References 56 publications

Interleukin-27 Induces a STAT1/3- and NF-κB-dependent Proinflammatory Cytokine Profile in Human Monocytes

Interleukin-27 Induces a STAT1/3- and NF-κB-dependent Proinflammatory Cytokine Profile in Human Monocytes

Suppression of CD4+T Lymphocyte Activationin Vitroand Experimental Encephalomyelitisin Vivoby the Phosphatidyl Inositol 3-Kinase Inhibitor PIK-75

miR‐124a inhibits the proliferation and inflammation in rheumatoid arthritis fibroblast‐like synoviocytes via targeting PIK3/NF‐κB pathway

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Suppression of CD4⁺T Lymphocyte Activationin Vitroand Experimental Encephalomyelitisin Vivoby the Phosphatidyl Inositol 3-Kinase Inhibitor PIK-75