Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human immunodeficiency virus, type 1 (HIV-1) promoter is known to be activated by proinflammatory cytokines and UV light. These stimuli also activate various members of the mitogen-activated protein kinase family, including JNK/SAPK and CSBP/p38. In HeLa cells containing an integrated HIV-1 long terminal repeat (LTR) -driven reporter, we now show that the specific p38 inhibitor, SB203580, inhibits activation of the HIV-1 LTR by interleukin-1, tumor necrosis factor, UV light, and osmotic stress. Inhibition was 70-90% in all but the case of tumor necrosis factor stimulation, where inhibition was 50%. Each of these stimuli activated p38, which was inhibited by SB203580 in vitro and in vivo with an IC50 (between 0.1 and 1 microM) similar to that required to inhibit transcription. In contrast, SB203580 had no effect on JNK, which was also activated by these stimuli. The NFkappaB sites in the HIV-1 LTR were required for a response to cytokines but not to UV, and SB203580 remained capable of inhibiting UV activation in the absence of the NFkappaB sites. Studies in which SB203580 was added at different times relative to UV stimulation suggested that the critical p38-mediated phosphorylation event occurred between 2 and 4 h after UV treatment. These data indicate that p38 is required for HIV-1 LTR activation but that the action of p38 is delayed, presumably due to substrate unavailability or inaccessibility.
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PMID:Activation of the HIV-1 long terminal repeat by cytokines and environmental stress requires an active CSBP/p38 MAP kinase. 894 70

The immunodeficiency present in patients with lepromatous leprosy is characterized by the limited proliferation of T lymphocytes, and is explained in part by the impaired synthesis of interleukin-2 (IL-2). Diacylglycerol (DAG) and calcium produce the activation of PKC, ERK and JNK kinases, implying a normal IL-2 response. Phorbol esters, such as PMA, can substitute for DAG and are mitogenic to human T and B cells activating several cytokine-encoding genes. Ionophore A23187 increases calcium permeability across the cellular membrane to the cytosol of lymphoid cells and is considered a co-mitogen of T lymphocytes. Here we report that: 1) PHA-activated T lymphocytes from LL patients can be separated in vitro into two groups: a) responders (R) with a stimulation index (SI) of > 10 and (b) nonresponders (NR) with a SI of < 10. 2) The proliferative responses of cells from LL(R), LL(NR) and normal subjects were measured after being stimulated with: I, PHA, PMA, PMA + I PHA + PMA and PHA + PMA + ionophore (PPI). The most important result occurs in LL(NR) patients whose cells did not respond to PHA stimulation but increased to normal levels of proliferation when they were stimulated with PMA. Furthermore, the three groups, (NR, R and normals) strongly increased their responses when they were incubated with PPi. 3) Finally, Il-2 concentrations in the supernatants of cultures of T lymphocytes from LL(NR), LL(R) and controls were relatively low when they were incubated with PHA or PMA, but the addition of ionophore to PMA and the combination of PHA + PMA strongly increased the production of IL-2 in all of them, reaching the optimum IL-2 concentration when PPI is used. It can be concluded that the use of PMA, analogous to DAG, and ionophore A23187 (calcium increaser) in cultures of mitogen-activated T lymphocytes from LL patients induced the expression of the IL-2 gene, thus correcting the inadequate proliferation of T cells from LL patients.
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PMID:Effect of phorbol myristate acetate (PMA) and ionophore A23187 on interleukin-2 levels and proliferation of activated T lymphocytes from patients with lepromatous leprosy. 920 56

We report that human immunodeficiency virus type 1 (HIV-1) has evolved a self-perpetuating mechanism to actively generate cells permissive for productive and cytopathic infection. Only activated T cells can be productively infected, which leads to their rapid depletion (2 x 10(9)/day in an infected individual). Establishment of productive HIV-1 infection therefore requires continual activations from the large pool of quiescent T cells. Tat protein, which is secreted by infected cells, activated uninfected quiescent T cells in vitro and in vivo. These Tat-activated uninfected cells became highly permissive for productive HIV-1 infection. Activation of primary T cells by Tat protein involved integrin receptors and was associated with activation of mitogen-activated protein kinases, including ERK1 and JNK kinase. Accordingly, these primary T cells progressed from G0 to the late G1 phase of the cell cycle.
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PMID:Tat protein induces self-perpetuating permissivity for productive HIV-1 infection. 922 24

Bruton's tyrosine kinase (Btk) plays crucial roles in B cell differentiation as well as mast cell activation through the high-affinity IgE receptor (FcepsilonRI). Defects in the btk gene lead to agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Mast cells from xid and btk null mice exhibit mild defects in degranulation and severe impairments in the production of proinflammatory cytokines upon FcepsilonRI cross-linking. Recent studies demonstrated the role of Btk in a sustained increase in intracellular calcium concentrations in response to antigen receptor stimulation. Btk is also involved in the activation of stress-activated protein kinases, JNK/SAPK1/2, and thereby regulates c-Jun and other transcription factors that are important in cytokine gene activation. Regulation of the JNK/SAPK activation pathway by Btk may be related to the proapoptotic function of Btk in the programmed cell death in these hematopoietic cells.
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PMID:Functions of Bruton's tyrosine kinase in mast and B cells. 1008 May 29

To study the role of MAPK cascades in the regulation of naturally occurring human immunodeficiency virus type 1 long terminal repeats (HIV-1 LTRs), we analyzed several HIV-1 LTRs from patients at different stages of disease progression. One of these naturally occurring HIV-1 LTRs contains an insertion termed the most frequent naturally occurring length polymorphism (MFNLP) and exhibited high inducibility upon T cell activation. We found that the protein kinase mixed lineage kinase 3/src-homology 3 domain-containing proline-rich kinase, a specific activator of the stress-activated protein kinase (SAPK)/JNK signaling pathway in T lymphocytes, induces high transcriptional activation of this promoter. Promoter inducibility is inhibited by the SAPK/JNK inhibitor, the JNK binding domain of the JNK interacting protein 1, and Tam-67 (N-terminal deletion mutant of c-Jun). In electrophoretic mobility shift assay, several protein complexes were found to bind to the MFNLP sequence in T cells. We identified AP-1 factors c-Fos and JunB as MFNLP-binding proteins, whose binding is abolished by introducing point mutations in the 3'-half of the MFNLP sequence. Introduction of these point mutations into the MFNLP containing HIV-1 LTR reduced src-homology 3 domain-containing proline-rich kinase -mediated transactivation. These data indicate that the AP-1-like binding site in the MFNLP sequence gives rise to a higher inducibility of natural HIV-LTRs by the SAPK/JNK signaling pathway.
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PMID:Transactivation of naturally occurring HIV-1 long terminal repeats by the JNK signaling pathway. The most frequent naturally occurring length polymorphism sequence introduces a novel binding site for AP-1 factors. 1076 60

The human immunodeficiency virus (HIV) Nef protein plays a critical role in AIDS pathogenesis by enhancing replication and survival of the virus within infected cells and by facilitating its spread in vivo. Most of the data obtained so far have been in experiments with endogenous Nef protein, so far overlooking the effects of exogenous soluble Nef protein. We used recombinant exogenous Nef proteins to activate nuclear transcription factors NF-kappaB and AP-1 in the promonocytic cell line U937. Exogenous SIV and HIV-1 Nef proteins activated NF-kappaB and AP-1 in a dose- and time-dependent manner. Activation of NF-kappaB by exogenous Nef was concomitant to the degradation of the inhibitor of NF-kappaB, IkappaBalpha. In agreement with increased AP-1 activation, a time- and dose-dependent increase in JNK activation was observed following treatment of U937 cells with exogenous Nef. Since exogenous Nef activates the transcription factors NF-kappaB and AP-1, which bind to the HIV-1 long terminal repeat (LTR), we investigated the effect of exogenous Nef on HIV-1 replication. We observed that exogenous Nef stimulated HIV-1 LTR via NF-kappaB activation in U937 cells and enhanced viral replication in the chronically infected promonocytic cells U1. Therefore, our results suggest that exogenous Nef could fuel the progression of the disease via stimulation of HIV-1 provirus present in such cellular reservoirs as mononuclear phagocytes in HIV-infected patients.
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PMID:Exogenous Nef protein activates NF-kappa B, AP-1, and c-Jun N-terminal kinase and stimulates HIV transcription in promonocytic cells. Role in AIDS pathogenesis. 1241 5

The CD4 molecule plays an essential role in mediating the transduction of intracellular signals by functioning as a coreceptor for the complex T cell receptor/CD3 and also acts as the primary receptor for human immunodeficiency virus (HIV). Several authors have shown evidence that jacalin, a plant lectin, binds to CD4 and inhibits in vitro HIV infection. We analyzed jacalin-induced intracellular signaling events in CD4(+) T cells and have shown that cell activation resulted in tyrosine phosphorylation of intracellular substrates p56(lck), p59(fyn), ZAP-70, p95 (vav), phospholipase C-gamma1, and ras activation, as assessed by conversion of ras guanosine 5'-diphosphate to ras guanosine 5'-triphosphate. We further examined extracellular regulated kinase (ERK) and c-jun NH(2)-terminal kinase (JNK) phosphorylation following stimulation with jacalin. The data indicate that the kinetics of JNK phosphorylation is delayed. Optimum phosphorylation of ERK2 was observed by 10 min, and that of JNK was observed by 30 min. Pretreatment with gp120 followed by stimulation with jacalin resulted in marked inhibition of all of the aforementioned intracellular events. The data presented here provide insight into the intracellular signaling events associated with the CD4 molecule-jacalin-gp120 interactions and HIV-induced CD4(+) T cell anergy. Jacalin may be used as a possible tool for the study of CD4-mediated signal transduction and HIV-impaired CD4(+) T cell activation.
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PMID:The lectin jacalin induces phosphorylation of ERK and JNK in CD4+ T cells. 1271 84

Myocardial dysfunction leading to dilated cardiomyopathy has been documented with surprisingly high frequency in human immunodeficiency virus (HIV)-infected individuals. p38 MAP kinase has been implicated as a mediator of myocardial dysfunction. We previously reported p38 MAP kinase activation by the HIV coat protein gp120 in neonatal rat cardiac myocytes. We now report the direct inotropic effects of HIV gp120 on adult rat ventricular myocytes (ARVM). ARVM were continuously superfused with gp120, and percent fractional shortening (FS) was determined by automated border detection and simultaneous intracellular ionized free Ca2+ concentration ([Ca2+]i) measured by fura 2-AM fluorescence: gp120 alone increased FS and increased [Ca2+]i within 5 min and then depressed FS without a decrease in [Ca2+]i by 20-60 min, which persisted for at least 2 h. Exposure of ARVM to gp120 also resulted in the phosphorylation of the upstream regulator of p38 MAP kinase MKK3/6, p38 MAP kinase itself, and its downstream effector, ATF-2, over a similar time course. ERK (p44/42) and JNK stress signaling pathways were not similarly activated. The effects of the p38 MAP kinase inhibitor were concentration dependent. SB-203580 (10 microM) blocked both p38 MAP kinase phosphorylation and the delayed negative inotropic effect of gp120. SB-203580 (5 microM) selectively blocked phosphorylation of ATF-2 without blocking the phosphorylation of MKK3/6 or p38 MAP kinase itself. SB-203580 (5 microM) administered before, with, or after gp120 blocked the negative inotropic effect of gp120 in ARVM. p38 MAP kinase activation may be a common stress-response mechanism contributing to myocardial dysfunction in HIV and other nonischemic as well as ischemic cardiomyopathies.
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PMID:p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes. 1466 Apr 88

Central nervous system (CNS) disease is a frequent complication of human immunodeficiency virus (HIV)-1 infection. Identification of cellular mechanisms that control virus replication and that mediate development of HIV-associated neuropathology will provide novel strategies for therapeutic intervention. The milieu of the CNS during HIV infection is extraordinarily complex because of infiltration of inflammatory cells and production of chemokines, cytokines, and neurotoxic molecules. Cells in the CNS must integrate signaling pathways activated simultaneously by products of virus replication and infiltrating immune cells. In this study, we examined activation of mitogen-activated protein kinases (MAPKs) in the CNS of simian immunodeficiency virus-infected macaques during acute, asymptomatic, and terminal infection. We demonstrate that significantly increased (P < 0.02) activation of ERK MAPK, typically associated with anti-apoptotic and neuroprotective pathways, occurs predominantly in astrocytes and immediately precedes suppression of virus replication and macrophage activation that occur after acute infection. In contrast, significantly increased activation of proapoptotic, neurodegenerative MAPKs JNK (P = 0.03; predominantly in macrophages/microglia), and p38 (P = 0.03; predominantly in neurons and astrocytes) after acute infection correlates with subsequent resurgent virus replication and development of neurological lesions. This shift from classically neuroprotective to neurodegenerative MAPK pathways suggests that agents that inhibit activation of JNK/p38 may be protective against HIV-associated CNS disease.
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PMID:Dysregulation of mitogen-activated protein kinase signaling pathways in simian immunodeficiency virus encephalitis. 1474 41

Progressive immunodeficiency in HIV infection is paralleled by a decrease in IL-12 production, a cytokine crucial for cellular immune function. Here we examine the molecular mechanisms by which HIV infection suppresses IL-12 p40 expression. HIV infection of THP-1 myeloid cells resulted in decreased LPS-induced nuclear factor binding to the NF-kappaB, AP-1, and Sp1 sites of the IL-12 p40 promoter. By site-directed mutagenesis we determined that each of these sites was necessary for transcriptional activation of the IL-12 p40 promoter. Binding of NF-kappaB p50, c-Rel, p65, Sp1, Sp3, c-Fos, and c-Jun proteins to their cognate nuclear factor binding sites was somewhat impaired by HV infection, although a role for other as yet unidentified factors cannot be dismissed. The cellular levels of these transcription factors were unaffected by HIV infection, with the exception of a decrease in expression of NF-kappaB p65, consistent with the observed decrease in its binding to the IL-12 p40 promoter following HIV infection. Analysis of regulation of upstream LPS-induced MAP kinases demonstrated impaired phosphorylation of JNK and p38 MAPK, and suppressed phosphorylation and degradation of IkappaBalpha following HIV infection. These results suggest that alterations in nuclear factor binding to numerous sites in the IL-12 p40 promoter, together may contribute to the suppression in IL-12 p40 transcription previously reported. These effects on nuclear factor binding may be a direct effect of HIV infection on the IL-12 p40 promoter, or may occur indirectly as a consequence of altered MAP kinase activation.
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PMID:Disruption of MAP kinase activation and nuclear factor binding to the IL-12 p40 promoter in HIV-infected myeloid cells. 1527 Aug 50


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