PI3K p110β Positively Regulates Lipopolysaccharide-Induced IL-12 Production in Human Macrophages and Dendritic Cells and JNK1 Plays a Novel Role

Utsugi, Mitsuyoshi; Dobashi, Kunio; Ono, Akiko; Ishizuka, Tamotsu; Matsuzaki, Shinichi; Hisada, Takeshi; Shimizu, Yasuo; Kawata, Takefumi; Aoki, Hiroaki; Kamide, Yosuke; Mori, Masatomo

doi:10.4049/jimmunol.0801352

Cited by 47 publications

(39 citation statements)

References 22 publications

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“…Although both LY and Rapa inhibited LPSinduced DC function, LY did so to a lesser extent, which could explain the reduced T cell stimulatory capacity observed for Rapabut not LY-treated DCs. These findings seem contradictory to some studies describing repression of cytokine production by PI3K and mTOR in moDC (16,36), but are in accordance with others (38,(54)(55)(56). These data indicate that although PI3K-PKB-mTOR signaling is not required for the acquisition of a DC phenotype or the survival of terminally differentiated CD34-derived myeloid DCs, this pathway may still be involved in the regulation of other important processes in these cells.…”

Section: Discussioncontrasting

confidence: 57%

Human CD34-Derived Myeloid Dendritic Cell Development Requires Intact Phosphatidylinositol 3-Kinase–Protein Kinase B–Mammalian Target of Rapamycin Signaling

Laar

Buitenhuis²,

Wensveen

et al. 2010

The Journal of Immunology

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Dendritic cells (DCs) are composed of different subsets that exhibit distinct functionality in the induction and regulation of immune responses. The myeloid DC subsets, including interstitial DCs and Langerhans cells (LCs), develop from CD34+ hematopoietic progenitors via direct DC precursors or monocytes. The molecular mechanisms regulating DC development are still largely unknown and mostly studied in mice. Phosphatidylinositol 3-kinase (PI3K) regulates multiple processes in myeloid cells. This study investigated the role of PI3K signaling in the development of human CD34-derived myeloid DCs. Pharmacologic inhibition of PI3K or one of its downstream targets mTOR reduced interstitial DC and LC numbers in vitro. Increased activity of this signaling module by introduction of constitutively active protein kinase B (PKB/c-Akt) increased the yields of human DC precursors in vitro as well as in transplanted β2-microglobulin−/− NOD/SCID mice in vivo. Signaling inhibition during differentiation did not affect the acquisition of a DC phenotype, whereas proliferation and survival strongly depended on intact PI3K–PKB–mTOR signaling. Interestingly, however, this pathway became redundant for survival regulation upon terminal differentiation, which was associated with an altered expression of apoptosis regulating genes. Although dispensable for costimulatory molecule expression, the PI3K–PKB–mTOR signaling module was required for other important processes associated with DC function, including Ag uptake, LPS-induced cytokine secretion, CCR7 expression, and T cell stimulation. Thus, PI3K–PKB–mTOR signaling plays a crucial role in the development of functional CD34-derived myeloid DCs. These findings could be used as a strategy to manipulate DC subset distribution and function to regulate immunity.

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Section: Discussioncontrasting

confidence: 57%

Human CD34-Derived Myeloid Dendritic Cell Development Requires Intact Phosphatidylinositol 3-Kinase–Protein Kinase B–Mammalian Target of Rapamycin Signaling

Laar

Buitenhuis²,

Wensveen

et al. 2010

The Journal of Immunology

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“…RPS6KB1 encodes a member of the ribosomal S6 kinase family of serine/threonine kinases and is part of the PI3K/AKT/ mTOR signaling pathway that plays a central role in a wide spectrum of cellular activities, including cell proliferation, survival, and differentiation. 70 The PI3K pathway is also involved in Toll-like receptor (TLR) signaling and release of cytokines from macrophages, 71 and a proxy SNP of TUBD1 rs1292053 has been associated with CRP. 72 KIF9 is a member of the kinesin family of genes related to microtubule binding and microtubule motor activity.…”

Section: Loci Involved In Other Cellular and Inflammatory Processesmentioning

confidence: 99%

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

Tajuddin

Schick

Eicher

et al. 2016

The American Journal of Human Genetics

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White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

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“…32,33 To determine the signaling mechanism(s) involved, we examined the effect of wortmannin, a pharmacologic global PI3K inhibitor, in TIMP-3-mediated down-regulation of IL-12. Pretreatment of imDCs with 500nM wortmannin could significantly augment LPS-induced IL-12 production ( Figure 5A).…”

Section: A Crucial Role Of Pi3k Signaling Pathway In Timp-3-mediated mentioning

confidence: 99%

Regulation of Th1/Th2 polarization by tissue inhibitor of metalloproteinase-3 via modulating dendritic cells

Shao

Ning

et al. 2012

Blood

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Tissue inhibitor of metalloproteinase-3 (TIMP-3) is one of a family of proteins inhibiting matrix metalloproteinases, which has also been identified as a mediator for checking inflammation. Meanwhile, it is well known that inflammation causes the activation of the immune response. However, it is not clear whether TIMP-3 plays a role in the immune system. In the present study, we demonstrated a novel function of TIMP-3 in Th1/Th2 polarization through its influence on the antigen-presenting cells. First, TIMP-3 was found strikingly up-regulated by IL-4 during the differentiation of human dendritic cells via the p38MAPK pathway. Second, the expression of costimulatory molecule-CD86 was repressed by TIMP-3. Besides, the induction of IL-12 in matured dendritic cells was significantly inhibited in a PI3K-dependent manner. IntroductionDendritic cells (DCs) are thought to be indispensable to initiate primary immune responses and play a pivotal role in linking the innate immunity and the adaptive immunity. 1,2 Their functions directly determine the outcome of T helper (Th) cell-mediated immune responses. 3,4 Normally, DCs reside in almost every tissue where they keep an immature state (imDCs) and serve as sentinels for the "dangerous" antigens. On stimulation with antigens or other signals, they undergo maturation and the matured DCs (mDCs) then migrate to the draining lymph nodes, where they present antigens to naive T cells. 5,6 In addition to their antigen presenting capability executed by the MHC class II molecules and the costimulatory molecules (CD40, CD80, and CD86), DCs also manipulate the nature and extent of the T cell-mediated immune responses through producing a variety of cytokines in response to the TLR ligands. 7 IL-12, which is deemed as a critical signal in T-cell polarization, together with IFN-␥, instructs naive T cell to shift toward a Th1 response, whereas IL-4 and a low level of IL-12 cause a Th2 response. In addition, the generation of regulatory T (Treg) cells requires 5,8,9 Therefore, the tissue environmental factors profoundly influence the adaptive immune responses through their modulation on DCs.Tissue inhibitors of metalloproteinases (TIMPs), specific inhibitors of matrix metalloproteinases (MMPs), consist of a family of 4 proteins that have been characterized so far. Independent of their inhibitory ability on MMPs, they also perform other biologic activities, such as promotion of cell proliferation, proapoptotic and antiapoptotic, and synaptic plasticity activities. 10,11 TIMP-3, a unique member of this family, is mainly sequestered to tissue extracellular matrix and is the only TIMP capable of inhibiting membrane bound MMPs, transmembrane MMPs, and sheddases, such as TNF-␣ converting enzyme. 12,13 TIMP-3 has been shown to act as a tumor suppressor in different cancer types, and loss of TIMP3 is closely associated with acquisition of tumorigenesis. 14-17 TIMP-3 can inhibit invasion and induce cell apoptosis in some specific cancer cell strains. [18][19][20][21][22] These observations indica...

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PI3K p110β Positively Regulates Lipopolysaccharide-Induced IL-12 Production in Human Macrophages and Dendritic Cells and JNK1 Plays a Novel Role

Cited by 47 publications

References 22 publications

Human CD34-Derived Myeloid Dendritic Cell Development Requires Intact Phosphatidylinositol 3-Kinase–Protein Kinase B–Mammalian Target of Rapamycin Signaling

Human CD34-Derived Myeloid Dendritic Cell Development Requires Intact Phosphatidylinositol 3-Kinase–Protein Kinase B–Mammalian Target of Rapamycin Signaling

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

Regulation of Th1/Th2 polarization by tissue inhibitor of metalloproteinase-3 via modulating dendritic cells

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