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At least 991 records · Page 55Linked to original sources
PubMed2002

Activation of IRS-2-mediated signal transduction by IGF-1, but not TGF-alpha or EGF, augments pancreatic beta-cell proliferation.

Transforming growth factor (TGF)-alpha- and epidermal growth factor (EGF)-induced signal transduction was directly compared with that of glucose and insulin-like growth factor-1 (IGF-1) in INS-1 cells. TGF-alpha/EGF transiently (<20 min) induced phosphorylation of extracellular-regulated kinase (Erk)-1/2 (>20-fold), glycogen synthase kinase (GSK)-3 (>10-fold), and protein kinase B (PKB) (Ser(473) and Thr(308)), but did not increase [(3)H]thymidine incorporation. In contrast, phosphorylation of Erk1/2, GSK-3, and PKB in response to glucose and IGF-1 was more prolonged (>24 h) and, though not as robust as TGF-alpha/EGF, did increase beta-cell proliferation. Phosphorylation of p70(S6K) was also increased by IGF-1/glucose, but not by TGF-alpha/EGF, despite upstream PKB activation. It was found that IGF-1 induced phosphatidylinositol 3-kinase (PI3K) association with insulin receptor substrate (IRS)-1 and -2 in a glucose-dependent manner, whereas TGF-alpha/EGF did not. The importance of specific IRS-2-mediated signaling events was emphasized in that adenoviral-mediated overexpression of IRS-2 further increased glucose/IGF-1-induced beta-cell proliferation (more than twofold; P < 0.05) compared with control or adenoviral-mediated IRS-1 overexpressing INS-1 cells. Neither IRS-1 nor IRS-2 overexpression induced a beta-cell proliferative response to TGF-alpha/EGF. Thus, a prolonged activation of Erk1/2 and PI3K signaling pathways is important in committing a beta-cell to a mitogenic event, and it is likely that this sustained activation is instigated by signal transduction occurring specifically through IRS-2.

Adenoviridae↗
PubMed2004

Prostaglandin E2 promotes the survival of bone marrow-derived dendritic cells.

Since dendritic cells (DC) participate in both innate and adaptive immunity, their survival and expansion is tightly controlled. Little is known about the mechanisms of DC apoptosis. PGE(2), an arachidonic acid metabolite, plays an essential role in DC migration. We propose a novel function for PGE(2) as a DC survival factor. Our studies demonstrate that PGE(2) protects DC in vitro against apoptosis induced by withdrawal of growth factors or ceramide. DC matured in conditions that inhibit endogenous PGE(2) release are highly susceptible to apoptosis and exogenous PGE(2) re-establishes the more resistant phenotype. The antiapoptotic effect is mediated through EP-2/EP-4 receptors and involves the PI3K --> Akt pathway. PGE(2) leads to increased phosphorylation of Akt, protection against mitochondrial membrane compromise, and decreased caspase 3 activity. Macroarray data indicate that PGE(2) leads to the down-regulation of a number of proapoptotic molecules, i.e., BAD, several caspases, and granzyme B. In vivo, higher numbers of immature and Ag-loaded CFSE-labeled DC are present in the draining lymph nodes of mice inoculated with PGE(2) receptor agonists, compared with animals treated with ibuprofen or controls injected with PBS. This suggests that PGE(2) acts as an endogenous antiapoptotic factor for DC and raises the possibility of using PGE(2) agonists to increase the survival of Ag-loaded DC following in vivo administration.

Animals↗
PubMed2004

Cutting edge: expression patterns of surface and soluble triggering receptor expressed on myeloid cells-1 in human endotoxemia.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently identified molecule involved in the amplification of inflammation. To determine the regulation of TREM-1, we studied TREM-1 expression and soluble TREM-1 plasma levels upon i.v. LPS challenge in healthy humans in vivo and in vitro. Granulocyte TREM-1 expression was high at baseline and immediately down-regulated upon LPS exposure along with an increase in soluble TREM-1. Monocytes displayed a gradual up-regulation of TREM-1 upon LPS in vivo and in vitro. In vitro studies extended these findings to highly purified lipoteichoic acid and Streptococcus pneumoniae. Nonbacterial TLR ligands such as polyinosine-polycytidylic acid and imidazoquinoline, as well as the TLR9 ligand CpG, did not impact TREM-1 expression. The LPS-induced alterations in TREM-1 surface expression were not a result of increased TNF-alpha or IL-10. Inhibitor studies disclosed a PI3K-dependent pathway in LPS-induced up-regulation of TREM-1 on monocytes, whereas MAPK played a limited role.

Cell Separation↗
PubMed2004

Rap1 signaling is required for suppression of Ras-generated reactive oxygen species and protection against oxidative stress in T lymphocytes.

Transient production of reactive oxygen species (ROS) plays an important role in optimizing transcriptional and proliferative responses to TCR signaling in T lymphocytes. Conversely, chronic oxidative stress leads to decreased proliferative responses and enhanced transcription of inflammatory gene products, and is thought to underlie the altered pathogenic behavior of T lymphocytes in some human diseases, such as rheumatoid arthritis (RA). Although the signaling mechanisms regulating ROS production in T lymphocytes has not been identified, activation of the small GTPase Ras has been shown to couple agonist stimulation to ROS production in other cell types. We find that Ras signaling via Ral stimulates ROS production in human T lymphocytes, and is required for TCR and phorbol ester-induced ROS production. The related small GTPase Rap1 suppresses agonist, Ras and Ral-dependent ROS production through a PI3K-dependent pathway, identifying a novel mechanism by which Rap1 can distally antagonize Ras signaling pathways. In synovial fluid T lymphocytes from RA patients we observed a high rate of endogenous ROS production, correlating with constitutive Ras activation and inhibition of Rap1 activation. Introduction of dominant-negative Ras into synovial fluid T cells restored redox balance, providing evidence that deregulated Ras and Rap1 signaling underlies oxidative stress and consequent altered T cell function observed in RA.

Humans↗
PubMed2005

The production of IL-1 receptor antagonist in IFN-beta-stimulated human monocytes depends on the activation of phosphatidylinositol 3-kinase but not of STAT1.

IFN-beta induces the production of secreted IL-1R antagonist (sIL-1Ra) without triggering synthesis of the agonist IL-1beta in human monocytes. This might account for its anti-inflammatory properties. Canonically, IFN-beta signals through activation of JAK/STAT pathway, although PI3K and MAPK have also been involved. In this study, the role of PI3K, MEK1, and STAT1 in IFN-beta-induced sIL-1Ra production is investigated in freshly isolated human blood monocytes. PI3K, but not MEK1 activation is essential for sIL-1Ra production in monocytes treated with IFN-beta, as demonstrated by using the respective inhibitors of PI3K and MEK1, Ly294002 and PD98059. The use of cycloheximide and actinomycin D shows that sIL-1Ra was an immediate early gene induced by IFN-beta and that PI3K was controlling sIL-1Ra gene transcription. Although both inhibitors of PI3K and MEK1 diminished the Ser(727) phosphorylation of STAT1 induced by IFN-beta, only Ly294002 inhibited sIL-1Ra production. Furthermore, the inhibition of STAT1-Ser(727) phosphorylation by Ly294002 did not affect STAT1 translocation, suggesting that STAT1 was not involved in sIL-1Ra gene induction. This was confirmed in monocytes that were transfected with small interfering RNA specifically targeting STAT1. Indeed, monocytes in which effective STAT1 gene knockdown was achieved were fully responsive to IFN-beta in terms of sIL-1Ra production. Taken together, the present data demonstrate that the induction of sIL-1Ra transcription and production by IFN-beta in human monocytes involved PI3K, but not STAT1 activation.

Active Transport, Cell Nucleus↗
PubMed2005

IL-15 activates telomerase and minimizes telomere loss and may preserve the replicative life span of memory CD8+ T cells in vitro.

The preservation of the replicative life span of memory CD8(+) T cells is vital for long-term immune protection. Although IL-15 plays a key role in the homeostasis of memory CD8(+) T cells, it is unknown whether IL-15 regulates the replicative life span of memory CD8(+) T cells. In this study, we report an analysis of telomerase expression and telomere length in human memory phenotype CD8(+) T cells maintained by IL-15 in vitro. We demonstrate that IL-15 is capable of activating telomerase in memory CD8(+) T cells via Jak3 and PI3K signaling pathways. Furthermore, IL-15 induces a sustained level of telomerase activity over long periods of time, and in turn minimizes telomere loss in memory CD8(+) T cells after substantial cell divisions. These findings suggest that IL-15 activates stable telomerase expression and compensates telomere loss in memory phenotype CD8(+) T cells, and that telomerase may play an important role in memory CD8(+) T cell homeostasis.

CD8-Positive T-Lymphocytes↗
PubMed2006

Thiocyanate-dependent induction of endothelial cell adhesion molecule expression by phagocyte peroxidases: a novel HOSCN-specific oxidant mechanism to amplify inflammation.

Both eosinophil peroxidase (EPO) and neutrophil myeloperoxidase (MPO) preferentially oxidize SCN(-) to generate HOSCN, a weak, sulfhydryl-reactive oxidant, as a major physiologic product. We here show that HOSCN is a uniquely potent phagocyte oxidant inducer of E-selectin, ICAM-1, and VCAM-1 expression in HUVEC as detected by Western blot and flow cytometry. EMSA and inhibitor studies show that HOSCN up-regulation of these adhesion molecules is transcriptionally mediated through a mechanism that is dependent upon activation of the NF-kappaB p65/p50 transcription factor and constitutively suppressed by PI3K-Akt pathway activity. HUVEC monolayers exposed to HOSCN bind 8-fold more neutrophils and 3- to 4-fold more Aml14.3D10 cells (a differentiated cell line model of mature eosinophils) than control monolayers. Blocking Ab studies confirm the involvement of E-selectin and ICAM-1 but not VCAM-1 in neutrophil adhesion and of all three in Aml14.3D10 adhesion. Intraperitoneal injection of HOSCN evoked an 8-fold increase in neutrophil peritoneal extravasation. In addition to NF-kappaB, HOSCN also activates the potentially proinflammatory transcription factors Stat4, CDP, GRE, CBF, Ets-1/PEA3, and TFIID, a pattern easily distinguishable from that induced by LPS. These results suggest that phagocyte peroxidases function to amplify inflammation through a novel, HOSCN-specific oxidant mechanism.

Cell Adhesion Molecules↗
PubMed2006

Oncostatin M-induced IL-6 expression in murine fibroblasts requires the activation of protein kinase Cdelta.

Oncostatin M (OSM) is an IL-6/LIF cytokine family member whose role has been identified in a range of biological activities in vitro, including up-regulation of inflammatory gene expression and regulation of connective tissue metabolism. However, the mechanisms through which OSM regulates cellular responses are not completely understood. In this study, we show that activation of the calcium-independent or novel protein kinase C (PKC) isoform PKCdelta is a critical event during OSM-mediated up-regulation of IL-6 expression in murine fibroblasts. The pan-PKC inhibitor GF109203X (bisindolylmaleimide I) reduced secretion of IL-6; however, use of Go6976, an inhibitor of calcium-dependent PKC enzymes, did not. The PKCdelta-selective inhibitory compound rottlerin abrogated expression of IL-6 transcript and protein, but only reduced PKCdelta activity when used at higher concentrations as determined by kinase activity assay, suggesting rottlerin may inhibit IL-6 expression in a PKCdelta-independent manner. However, silencing of PKCdelta protein expression, but not the related novel isoform PKCepsilon, by use of RNA interference (i.e., small interfering RNA) demonstrated that PKCdelta is required for murine OSM (mOSM) induction of IL-6 protein secretion. Furthermore, inhibition of PI3K by use of LY294002 reduces expression of IL-6 at both the mRNA and protein level in murine fibroblasts, and we suggest that PI3K is required for activation of PKCdelta. Knockdown of phosphoinositide-dependent kinases PDK-1 or Akt1 using small interfering RNA strategies did not influence mOSM-induced IL-6 expression, suggesting mOSM uses a PI3K-PKCdelta pathway of activation independent of these kinases. Our findings illustrate a novel signaling network used by mOSM that may be important for its mediation of inflammatory processes.

Animals↗
PubMed2006

The p110delta isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells.

The role of PI3K in T cell activation and costimulation has been controversial. We previously reported that a kinase-inactivating mutation (D910A) in the p110delta isoform of PI3K results in normal T cell development, but impaired TCR-stimulated cell proliferation in vitro. This proliferative defect can be overcome by providing CD28 costimulation, which raises the question as to whether p110delta activity plays a role in T cell activation in vivo, which occurs primarily in the context of costimulation. In this study, we show that the PI3K signaling pathway in CD28-costimulated p110delta D910A/D910A T cells is impaired, but that ERK phosphorylation and NF-kappaB nuclear translocation are unaffected. Under in vitro conditions of physiological Ag presentation and costimulation, p110delta D910A/D910A T cells showed normal survival, but underwent fewer divisions. Differentiation along the Th1 and Th2 lineages was impaired in p110delta D910A/D910A T cells and could not be rescued by exogenous cytokines in vitro. Adoptive transfer and immunization experiments in mice revealed that clonal expansion and differentiation in response to Ag and physiological costimulation were also compromised. Thus, p110delta contributes significantly to Th cell expansion and differentiation in vitro and in vivo, also in the context of CD28 costimulation.

Adoptive Transfer↗
PubMed2006

Human tumor mutants in the p110alpha subunit of PI3K.

The PI3K-Akt pathway is frequently upregulated in human tumors. Recently, somatic mutations of PIK3CA, encoding p110alpha catalytic subunit of Class IA PI3Ks, have been found in various cancers. The two most common types of p110alpha mutants, those in the helical and kinase domains, have been shown to be very potent in Akt activation and oncogenic transformation by several groups. Notably these common mutations may not enhance recruitment of p110alpha to the plasma membrane where its substrates are located. We have investigated the effect of membrane localization on common PIK3CA tumor mutants via myristoylation. In addition we have studied a third class of less frequent mutants in the p85-binding domain, in an attempt to gain insight into p85's inhibitory effect on p110alpha. This article briefly reviews and extends the literature on mutant forms of p110alpha.

Class I Phosphatidylinositol 3-Kinases↗
PubMed1999

[Implication of growth factor receptor signaling for axotomized motor neuron survival after nerve injury].

Motor neurons are able to survive even after nerve injury. In order to reveal the molecular basis underlying this survival mechanism, we carried out gene screening using Differential Display PCR method and a cDNA library derived from rat injured hypoglossal nuclei. This gene hunting provided us with some of the parts of the molecular mechanism for nerve regeneration, among which intracellular signaling molecules, in particular downstream growth factor receptors, seemed very important. We therefore examined the significance of the molecules by using adenovirus mediated gene transfer system, and concluded that PI3K-Akt pathway could be one of the important pathways by which injured motor neurons survive and regenerate.

Adenoviridae↗
PubMed2001

Correlation between loss of PTEN expression and Akt phosphorylation in endometrial carcinoma.

The tumor suppressor PTEN acts as a lipid phosphatase, regulates the phosphatidylinositol 3-kinase (PI3K)/Akt-signaling pathway, and modulates cell cycle progression and cell survival. Somatic mutations of PTEN have been reported in a variety of cancers, especially in endometrial carcinoma. To clarify whether and how PTEN and the PI3K/Akt pathway relates to endometrial carcinoma, we examined the expression of those pathway-related proteins in patients with endometrial carcinoma. Of 103 endometrial carcinomas, 37 (36%) showed negative immunohistochemical staining of PTEN. Western blotting revealed that the expression of PTEN in PTEN-negative cases was significantly lower compared with that in positive cases. In contrast, phospho-Akt level in negative cases was significantly higher. We found a significant inverse correlation between PTEN and phospho-Akt (r = -0.796). The expression of phospho-Bad was greater in negative cases, suggesting that Bad might be a target for AKT: The present study demonstrates the phosphorylation of Akt accompanied by the loss of PTEN in clinical specimens of endometrial carcinomas.

Carrier Proteins↗
PubMed2002

Involvement of type I protein kinase A in the differentiation of L6 myoblast in conjunction with phosphatidylinositol 3-kinase.

To investigate the role of protein kinase A (PKA) (EC 2.7.1.37) in myogenesis, PKA activity was closely monitored during the differentiation of L6 rat skeletal myoblasts. As the differentiation proceeded, total PKA activity increased about 2-3 fold, and the protein levels of PKA RIalpha and Calpha subunits increased about 3-4 fold. We then looked at the effect of the specific inhibitor for PKA, N-[2-(p-bromocinnamy-lamino)-ethyl]-5-isoquinoline-sulfonamide (H89), on the differentiation of L6 myoblasts. H89 completely blocked the myotube formation and abolished the up-regulation of RIalpha and Ca. This inhibitory effect of H89 was dose-dependent and could be reversed upon removal of H89 from the culture medium. Furthermore, we demonstrated that specific inhibitors of phosphatidylinositol 3-kinase (PI3K), wortmannin, and LY294002 blocked the myotube formation and abolished the increase of PKA activity, which normally accompanied the differentiation of myoblasts. These results suggest that type I PKA may play a functional role(s) in the differentiation of myoblast as a putative downstream effector of the PI3K signaling pathway.

Androstadienes↗
PubMed2003

Overexpression of the NF2 gene inhibits schwannoma cell proliferation through promoting PDGFR degradation.

The loss of NF2 gene function leads to vestibular nerve schwannoma formation in humans. The NF2 gene product, Merlin/Schwannomin, has recently been found to interact with the two PDZ domains containing protein EBP50/NHE-RF, which is itself known to interact with the PDGF receptor (PDGFR) in several cell types. In this study, an up-regulation of both PDGFR and EBP50/NHE-RF, and an interaction of both proteins were found in primary human schwannoma tissue. Furthermore, using an adenoviral vector mediated gene transfer technique, changes in the phenotypic characteristics after NF2 gene restoration in a newly established NF2 gene-mutated human schwannoma cell line (HEI 193) were investigated. The overexpression of Merlin/Schwannomin in HEI 193 led to an inhibition of cell proliferation under serum-free conditions. Upon PDGF stimulation in culture, Merlin/Schwannomin appeared to inhibit the activation of the MAPK and PI3K signaling pathways, impinging on the phosphorylation of Erk 1/2 and Akt, respectively. The data also show that PDGFR is more rapidly internalized by the schwannoma cells overexpressing NF2. Therefore, this process is suggested as a model for a mechanism of Merlin/Schwannomin tumor suppressor function, which intermediates acceleration of the cell surface growth factor degradation.

Adenoviridae↗
PubMed2003

[Cell biological mechanism involved in the effect of sodium selenite on improving insulin sensitivity].

OBJECTIVE: To study the cell biological mechanism of sodium selenite improving insulin sensitivity in pubertal rats with insulin resistance. METHODS: The content of inositol 1,4,5-trisphosphate (IP3) was examined by anion resin chromatography, and mRNA levels of phosphatidylinositol 3-kinase regulatory subunits (PI3Kp85 alpha) and Se-P were detected by RT-PCR in hepatocyte isolated from pubertal rats with insulin resistance. RESULTS: The mRNA levels of Se-P and PI3Kp85 alpha and content of IP3 in isolated hepatocyte decreased in pubertal male rats with insulin resistance. The above indices increased and reached normal level in rats supplied with selenium. The response to insulin stimulation in isolated hepatocyte in rats with selenium supply was similar to that in the control group, and both groups had higher response than those with high-fat diet. Alone when inhibited by wortmannin, the concentration of IP3 increased slightly in rats with selenium supply, but still was lower than that in the control group. CONCLUSIONS: These results indicate that the effect of selenium improving insulin sensitivity may be related to phosphatidylinositol PI3K signalling pathway. The effect of regulation of IP3 by selenium is not as effective as that by insulin, which may explain the difference of effect between selenium and insulin.

Animals↗
PubMed2005

[Exploration of ganglioside GM1 as an activation marker on T cells].

AIM: To compare and analyze the patterns of ganglioside GM1 and CD69 expressions on activated gammadeltaT cells and CD3(+) T cells from human peripheral blood. METHODS: PBMCs were stimulated in vitro with anti-CD3 mAb or Mycobacterium tuberculosis antigen (Mtb-Ag). In some experimental groups, PBMCs were pretreated with different inhibitors of signal transduction pathway before stimulation. The expressions of GM1 or CD69 on gammadeltaT and CD3(+) T cells at different time points after stimulation were measured by flow cytometry (FCM). RESULTS: GM1 appeared on gammadeltaT cells at 30 min after stimulation with Mtb-Ag and retained a higher level with the lapse of time; whereas CD69 expression appeared at 3 h after stimulation and reached peak at 24 h, and then decreased gradually to the resting level on day 6 after stimulation. The expressions of CD69 and GM1 on CD3(+) T cells stimulated with anti-CD3 mAb were similar to those on gammadeltaT cells. The expression of GM1 on gammadeltaT cells was inhibited by pretreatment with PD98059 or LY294002. PMA increased the expression of GM1. CONCLUSION: GM1 can serve as a novel marker of activated T cells. During the activation of T cells, the dynamic expression of GM1 was different from that of CD69, a very early activation antigen. The Ras-Erk signal transduction pathway and PI3K and PKC might be involved in the expression of GM1.

Antibodies, Monoclonal↗
PubMed2005

PDGF alpha-receptor signal strength controls an RTK rheostat that integrates phosphoinositol 3'-kinase and phospholipase Cgamma pathways during oligodendrocyte maturation.

Receptors with tyrosine kinase activity (RTKs) control tissue growth and development in metazoans. How they generate cell-specific responses remains essentially unknown; one model proposes that distinct RTKs activate different second-messenger pathways, whereas a second proposes that all RTKs deliver a generic "go" signal to these pathways that is uniquely interpreted by downstream, cell-specific response competence factors. We examine pathway activation and pathway-specific responses downstream of PDGFalpha receptors, whose expression in the developing CNS identifies oligodendrocyte progenitor cells (OPCs) and whose activation controls OPC proliferation, migration, survival, and maturation. PDGFRalpha-null mice die in utero, and OPCs that emerge before their demise have migration and proliferation defects and rapidly differentiate into postmitotic oligodendrocytes in vitro. OPCs from hemizygous mice also undergo precocious differentiation, indicating a role for PDGFRalpha gene dosage in timing OPC maturation. The rescue of PDGFRalpha-null OPCs with PDGFRalpha transgenes revealed specific roles for the phosphatidylinositol 3-kinase (PI3K) and phospholipase Cgamma (PLCgamma) pathways and a distinct ligand concentration dependence. Activation of the PI3K pathway is required for PDGFRalpha-induced migration, whereas activation of both PI3K and PLCgamma are required for PDGFRalpha-induced proliferation. For proliferation, PI3K activation is required at low ligand concentration, whereas PLCgamma is required at high signal strength. Dose-response studies further demonstrate that PDGFRalpha activates PI3K at low ligand concentrations, whereas PLCgamma is activated at high signal strength. Thus, PDGFRalpha signaling acts like a rheostat rather than generic ON switch, with signal strength dictating pathway activation during OPC maturation.

Age Factors↗
PubMed2004

The role of the p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and phosphoinositide-3-OH kinase signal transduction pathways in CD40 ligand-induced dendritic cell activation and expansion of virus-specific CD8+ T cell memory responses.

Mature dendritic cells (DCs) are central to the development of optimal T cell immune responses. CD40 ligand (CD40L, CD154) is one of the most potent maturation stimuli for immature DCs. We studied the role of three signaling pathways, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and phosphoinositide-3-OH kinase (PI3K), in CD40L-induced monocyte-derived DC activation, survival, and expansion of virus-specific CD8(+) T cell responses. p38 MAPK pathway was critical for CD40L-mediated up-regulation of CD83, a marker of DC maturation. CD40L-induced monocyte-derived DC IL-12 production was mediated by both the p38 MAPK and PI3K pathways. CD40L-mediated DC survival was mostly mediated by the PI3K pathway, with smaller contributions by p38 MAPK and ERK pathways. Finally, the p38 MAPK pathway was most important in mediating CD40L-stimulated DCs to induce strong allogeneic responses as well as expanding virus-specific memory CD8(+) T cell responses. Thus, although the p38 MAPK, PI3K, and ERK pathways independently affect various parameters of DC maturation induced by CD40L, the p38 MAPK pathway within CD40L-conditioned DCs is the most important pathway to maximally elicit T cell immune responses. This pathway should be exploited in vivo to either completely suppress or enhance CD8(+) T cell immune responses.

CD40 Ligand↗