Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-alpha (TNF) induces clustering of theca-interstitial cells (TIC) isolated from immature, hypophysectomized rats, while inhibiting luteinizing hormone (LH)-stimulated androstenedione in vitro. Stimulators of PKC, 1-oleoyl-2-acetyl-sn-glycerol (OAG, 50 and 100 microM) and phorbol-12-myristate-13-acetate (PMA, 50 nM), caused TIC clustering by 6 days in vitro. Clustering induced by these compounds resembled that induced by TNF. The protein kinase inhibitor, staurosporine at 1 and 10 nM, impaired TNF-induced TIC clustering for 6 days, as did the protein kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperizine dihydrochloride (H-7); conversely, the protein kinase inhibitor, chelerythrine chloride (0.1, 1.0 or 10 microM), did not attenuate TNF-directed clustering. The protein kinase inhibitors did not reverse the suppression of LH-stimulated androstenedione by TNF. Inhibitors of the EGF receptor PTK, A23 (10, 50, or 100 microM) and A46 (0.1, 1.0, 10, or 50 microM), impaired TNF-induced TIC clustering, while TNF suppression of LH-directed androstenedione was unaffected. EGF-induced TIC clustering was also impaired by A46, while A23 was less effective. Both A23 and A46 blocked EGF attenuation of LH-directed androstenedione after 4 days. When challenged with TNF (1 ng/ml) or PMA (50 nM), PKC activity increased in TIC. A23 (50 microM) and A46 (10 microM) each alone blocked the TNF-associated increase in PKC activity; however, PKC activity attributable to PMA was unaffected by A46. Together, these results suggest that TNF-induced TIC clustering involves activation of PTK which directs subsequent increases in PKC activity; however, mechanisms by which TNF inhibits LH-stimulated steroidogenesis remains elusive.
 ...
PMID:Involvement of protein kinase C and protein tyrosine kinase pathways in tumor necrosis factor-alpha-induced clustering of ovarian theca-interstitial cells. 814 4

We observe that highly purified (> or = 97% pure) gamma/delta T cells isolated from normal peripheral blood proliferate to bacterial toxin supperantigens SEA, SEB, SED, and TSST-1. MHC class II molecules were necessary and sufficient for the recognition of superantigens by gamma/delta T cells because MHC Class II deficient B cell line failed to support the proliferation of gamma/delta T cells to toxins and murine L cells transfected with HLA-DR but not untransfected cells were capable of presenting toxins to gamma/delta T cells. As in the case with alpha/beta T cells, bacterial superantigens synergized with PMA in causing the proliferation of purified gamma/delta T cells rigorously depleted of accessory cells. Together, our findings suggest that gamma/delta T cells recognize and respond to bacterial superantigens in a manner similar to alpha/beta T cells.
 ...
PMID:Bacterial superantigens induce the proliferation of resting gamma/delta receptor bearing T cells. 854 36

An important aspect of human immunodeficiency virus (HIV-1) infection is the regulation of its expression by nuclear factor kappa B (NF-kappa B) through redox-controlled signal transduction pathways. In this study, we demonstrate that iron chelation by deferoxamine (DFO) protects against the cytotoxic and reactivating effects of hydrogen peroxide (H2O2). These protective effects were observed both in lymphocytic (ACH-2) and promonocytic (U1) cells latently infected by HIV-1. Concomitantly, NF-kappa B activation by H2O2, when followed by gel retardation assay, was decreased in the DFO-treated U1 and ACH-2 cells. This latter DFO-mediated effect was specific, as DFO did not clearly affect AP-1 DNA-binding activity when studied after H2O2-induced stress. More importantly, DFO protected against the H2O2-induced activation of HIV-1 as evidenced by reverse transcriptase activity in the supernatant. DFO also protected against PMA-induced NF-kappa B activation as well as TNF-alpha-induced HIV-1 activation. Furthermore, DFO attenuated the p24 response in PBMC infected with HIV-1 and stimulated with IL-2. These different effects of DFO were obtained at DFO concentrations lower than 5 microM. Other chemically unrelated iron chelators also provided protection against cytotoxicity, NF-kappa B activation, and HIV-1 activation in U1 cells challenged with H2O2.
 ...
PMID:Iron chelation decreases NF-kappa B and HIV type 1 activation due to oxidative stress. 855 2

TCR engagement stimulates the activation of the protein kinase Raf-1. Active Raf-1 phosphorylates and activates the mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase kinase 1 (MEK1), which in turn phosphorylates and activates the MAP kinases/extracellular signal regulated kinases, ERK1 and ERK2. Raf-1 activity promotes IL-2 production in activated T lymphocytes. Therefore, we sought to determine whether MEK1 and ERK activities also stimulate IL-2 gene transcription. Expression of constitutively active Raf-1 or MEK1 in Jurkat T cells enhanced the stimulation of IL-2 promoter-driven transcription stimulated by a calcium ionophore and PMA, and together with a calcium ionophore the expression of each protein was sufficient to stimulate NF-AT activity. Expression of MEK1-interfering mutants inhibited the stimulation of IL-2 promoter-driven transcription and blocked the ability of constitutively active Ras and Raf-1 to costimulate NF-AT activity with a calcium ionophore. Expression of the MAP kinase-specific phosphatase, MKP-1, which blocks ERK activation, inhibited IL-2 promoter and NF-AT-driven transcription stimulated by a calcium ionophore and PMA, and in addition, MKP-1 neutralized the transcriptional enhancement caused by active Raf-1 and MEK1 expression. We conclude that the MAP kinase signal transduction pathway consisting of Raf-1, MEK1, and ERK1 and ERK2 functions in the stimulation IL-2 gene transcription in activated T lymphocytes.
 ...
PMID:MEK1 and the extracellular signal-regulated kinases are required for the stimulation of IL-2 gene transcription in T cells. 855 75

We had previously shown that chronically infected ACH-2 cells (HIVLAI) could be superinfected with HIVRF, that the frequency of superinfection increased with time, and that the transcription of the superinfecting virus exceeded that of the host HIVLAI provirus. In contrast, ACH-2 cells superinfected with a nef-substituted neomycin-resistant (proNEO) provirus were not detectable by DNA polymerase chain reaction (PCR) until geneticin (G418) was added, suggesting that the ability to propagate progressively in culture may be HIV strain specific. Clonal populations of ACH-2 superinfected with proNEO did not demonstrate preferential transcription of the superinfecting virus. However, clones of ACH-2 superinfected with HIVRF (ACH2/RF) showed a preponderance of HIVRF transcripts similar to that seen in bulk populations. Induction of the superinfecting virus by phorbol ester (PMA) occurred more rapidly than the hose provirus and did not equalize transcriptional activity. PCR-derived long terminal repeat (LTR) fragments and Tat cDNAs from A3.01 cells acutely infected with HIVRF or from ACH-2 cells were sequenced and tested for transactivation. The HIVLAI LTR was two to three times more Tat-responsive than the HIVRF LTR. TatRF was two to three times more transcriptionally active on either LTR than TatLAI. Demethylation with 5-azacytidine did not significantly affect HIV expression from the HIVLAI host provirus of superinfected ACH2/RF cell clones. These data suggest that the mechanism of preferential transcription in HIVRF superinfected ACH2/RF may be attributed to the Tat/TAR axis and the effect of the specific locus of host proviral integration.
 ...
PMID:Transcriptional effects of superinfection in HIV chronically infected T cells: studies in dually infected clones. 867 41

We have recently shown that ascorbic acid (AA) suppresses the production of HIV in a latently infected T-lymphocytic cell line (ACH-2) following stimulation with the tumor promoter, PMA. To evaluate the effect of ascorbic acid on virus activation following treatment with inflammatory cytokine, we tested tumor necrosis factor alpha (TNF-alpha) whose levels are elevated in patients with HIV/AIDS. ACH-2 cultures, pretreated with various nontoxic concentrations of ascorbate or AZT were stimulated for 2 h with TNF-alpha, and incubated further with fresh supplements of ascorbate or AZT. At 24 to 48 h post-treatment, the RT activity released into culture supernatant was determined. Results showed that TNF-alpha alone caused approximately 13- to 16-fold stimulation in the level of extracellular RT. Pretreatment with ascorbic acid at 200 micrograms/ml caused a little more than about 2- to 4-fold reduction in extracellular RT levels. Most remarkably, exposure to 300 micrograms/ml ascorbate resulted in approximately 5- to 10-fold lowering of the extra-cellular RT titer. In contrast, no significant suppression in extracellular RT levels was seen with concentrations of AZT in the range of 1-5 micrograms/ml.
 ...
PMID:Ascorbate effect on cytokine stimulation of HIV production. 874 52

In this study, we examined the effect of TNF-alpha on mesangial cell gene expression of M-CSF, a colony-stimulating factor associated with monocyte differentiation into macrophages and proliferation. Incubation of mesangial cells with TNF-alpha-stimulated mRNA expression and protein synthesis of M-CSF. Mesangial cell activation with PMA, a PKC activator, stimulated M-CSF mRNA expression while PKC depletion decreased M-CSF mRNA expression to control levels. Stimulation of PKC-depleted mesangial cells with either PMA or TNF-alpha inhibited M-CSF mRNA transcripts. Preincubation of mesangial cells with calphostin C, a PKC inhibitor, reduced both PMA- and TNF-alpha-induced M-CSF mRNA transcripts. Specific protein tyrosine kinase inhibitors blocked TNF-alpha-induced mesangial cell M-CSF mRNA expression. Additional studies showed that pertussis toxin, isoproterenol, and dibutyryl (db)cAMP did not induce mesangial cell M-CSF gene expression. However, coincubation of mesangial cells with TNF-alpha and either dbcAMP, forskolin, or pertussis toxin inhibited TNF-alpha-induced M-CSF gene expression. Finally, TNF-alpha-activated mesangial cell conditioned media stimulated monocyte/macrophage proliferation dose-dependently and was prevented by using anti-M-CSF. These data suggested that M-CSF can regulate monocyte differentiation into macrophages and proliferation within the mesangium induced by proinflammatory cytokines such as TNF-alpha. These cellular events appeared to be modulated by signal transduction pathways mediated by PKC and PTK.
 ...
PMID:Activation of mesangial cells with TNF-alpha stimulates M-CSF gene expression and monocyte proliferation: evidence for involvement of protein kinase C and protein tyrosine kinase. 878 64

Acute HIV-1 infection of H9 and C8166 cultures has been shown to be suppressed by certain flavonoids, and evidence for inhibition of HIV-1 protease, integrase, and reverse transcriptase by flavonoids also exists. The present aim was to determine whether flavonoids inhibit HIV-1 activation in models of latent infection. By screening flavonoids from six different classes, three structurally related compounds (chrysin, acacetin, and apigenin) were identified that inhibited HIV expression in TNF-alpha-treated OM-10.1 cultures. The three compounds had favorable potencies against HIV activation in relation to their growth inhibitory effects (therapeutic index 5-10). Chrysin also inhibited HIV expression in response to PMA in OM-10.1 cells, in ACH-2 cells stimulated with either TNF-alpha or PMA, and in 8E5 cultures. Furthermore, return to viral latency in OM-10.1 cells previously exposed to TNF-alpha occurred over a shorter time interval when chrysin was added. The inhibition of HIV activation was not dependent on preincubation with flavonoids relative to TNF, and was characterized by a lack of HIV RNA accumulation by Northern analysis. Gel-shift experiments revealed that NF-kappa B activation after TNF-alpha treatment was not inhibited by these agents, suggesting that some other critical factor(s) needed for viral transcription was being affected. These findings indicate that flavonoids inhibit HIV-1 activation via a novel mechanism, and that these agents are potential candidates for therapeutic strategies aimed at maintaining a cellular state of HIV-1 latency.
 ...
PMID:Inhibition of HIV activation in latently infected cells by flavonoid compounds. 882 17

Cytokines may have clinical utility as therapeutic agents for human immunodeficiency virus type 1 (HIV-1) infection and as an adjuvant for vaccines. The effect of interleukin-12 (IL-12) and IL-15 on in vitro HIV-1 replication was investigated. IL-12 and IL-15 at doses up to 10 ng/ml had little effect on basal HIV-1 p24 antigen production by chronically HIV-infected T (ACH-2) and monocytic (U1) cell lines. For ACH-2 cells stimulated with phorbol 12-myristate 13-acetate (PMA; 50 ng/ml), IL-12 and IL-15 significantly increased p24 antigen production by 20 and 30%, respectively (n = 6). In contrast, IL-12 and IL-15 (10 ng/ml) treatment of PMA-stimulated U1 cells decreased p24 antigen production by 16 and 15%, respectively (n = 6). We next studied the effect of IL-12 and IL-15 on HIV-infected peripheral blood mononuclear cells (PBMCs). In 10 HIV-seropositive patients' PBMCs cocultured with mitogen-activated HIV-seronegative donor cells, two patterns of p24 antigen production were observed in response to IL-2: low (p24 antigen production < 10(3) pg/ml; n = 8) and high (p24 antigen production > 10(3) pg/ml; n = 2) response. For the low-response pattern, IL-12 and IL-15 increased viral replication by 97-fold and 100-fold, respectively (P = 0.05 and 0.004, respectively). For the high-response pattern, both IL-12 and IL-15 suppressed HIV replication. The effect of IL-2, IL-12, and IL-15 on acute in vitro infection by HIV-1JRCSF was also examined. IL-12 did not increase p24 antigen production above basal levels while IL-2 and IL-15 significantly enhanced p24 antigen production (by approximately 2-fold). In conclusion, IL-12 and IL-15 may have differential effects on latent and acute HIV infection, and their ability to enhance HIV production may depend on cell activation. Thus, the use of these cytokines may be dictated by the clinical state of the patient.
 ...
PMID:Differential effects of interleukin-12, interleukin-15, and interleukin-2 on human immunodeficiency virus type 1 replication in vitro. 887 33

Peripheral blood mononuclear cells from 16 children with atopic disease (range of IgE levels: 33 - 2892 kU/l) and 12 age matched controls were stimulated either with mAbs specific for CD3, CD2, CD3 plus CD28, CD2 plus CD28, with Tetanus Toxoid, SEA, or PHA plus PMA and their cell proliferation was determined. In addition, their cytokine production (IL2, IL4, IL10, IFN gamma) following selected stimuli was measured. We found that the cells from atopics proliferated significantly better in response to CD2 stimulation than control cells, with no difference in response to CD3 or SEA stimulation. Furthermore, cells from atopics produced significantly higher amounts of IL4 than cells from controls, a difference most pronounced following CD2 plus CD28 stimulation. No differential production was found for IL10 and IFN gamma. We conclude that in atopic children with moderately elevated IgE a hyperreactivity of the CD2 pathway of stimulation and a clear elevation of IL4 but not of IL10 or IFN gamma production can be demonstrated.
 ...
PMID:Enhanced production of IL4 but not of IFN gamma and IL 10 by peripheral blood mononuclear cells from atopic children in response to CD2 plus CD28 stimulation. 890 57


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>