Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stromal-derived cell factor-1 alpha (SDF-1 alpha; CXCL12) and its receptor, CXCR4, are constitutively expressed on neuroepithelial cells and are believed to be involved in both development and pathological processes, such as AIDS-associated neurologic disorders. Here, we demonstrate that SDF-1 alpha activates NF-kappa B, stimulates production of chemokines and cytokines, and induces cell death in primary astrocytes, effects that depend on ongoing secretion of TNF-alpha. SDF-1 alpha upregulated TNF-alpha mRNA and protein secretion, as well as TNF receptor 2 expression. TNF-alpha treatment mimicked SDF-1 alpha induction of NF-kappa B, IL-1 alpha/beta, and RANTES, as well as cell death; neutralizing antibodies against TNF-alpha opposed these responses. We also found that SDF-1 alpha activated Erk1 and Erk2 (Erk1/2) MAPK in a biphasic fashion. Early Erk1/2 activation was stimulated directly by SDF-1 alpha and late activation was mediated by TNF-alpha. PD98059 suppression of early Erk1/2 activation correlated with reduction of SDF-1 alpha-induced TNF-alpha expression. Late Erk1/2 activation was involved in TNF-alpha-stimulated NF-kappa B activation and cytokine induction. SDF-1 alpha was induced in reactive CXCR4-positive astrocytes near axotomized spinal cord motor neurons, consistent with autocrine SDF-1/CXCR4 signaling in these cells. We propose that these novel effects of SDF-1 alpha are relevant to the pathogenic and developmental roles of SDF-1 alpha in the CNS.
 ...
PMID:TNF-alpha mediates SDF-1 alpha-induced NF-kappa B activation and cytotoxic effects in primary astrocytes. 1148 36

Aminooxypentane (AOP)-RANTES is a potent inhibitor of nonsyncytium-inducing (NSI), CCR5-tropic (R5) human immunodeficiency virus type 1 (HIV-1) isolates. Although classical chemotactic responses are not induced in primary leukocytes by AOP-RANTES, recent studies suggest that a remnant of cell signaling occurs upon binding of receptor to this compound. We have detected a breakthrough of NSI/R5 replication from the inhibitory effects of high AOP-RANTES concentrations (<100 nM). A stimulation of different primary syncytium-inducing (SI), CXCR4-tropic (X4) HIV-1 isolates was also observed in the presence of AOP-RANTES. This stimulation was also observed after 110 h in PCR and RT-PCR for minus-strand strong-stop DNA and unspliced and multiply spliced RNA, respectively. However, there was significant variability between different SI/X4 or NSI/R5 HIV-1 isolates with regard to this AOP-RANTES-mediated stimulation or breakthrough, respectively. To further define the mechanism(s) responsible for this AOP-RANTES effect, we performed detailed retroviral replication studies with an NSI/R5 (B-92BR021) and SI/X4 (D-92UG021) HIV-1 isolate in the presence of the drug. Treatment of peripheral blood mononuclear cells with 125 nM AOP-RANTES and virus did not alter coreceptor expression, HIV-1 entry, reverse transcription, or mRNA transcription from the long terminal repeat, but it did result in increased HIV-1 integration. This AOP-RANTES-mediated increase in HIV-1 integration was diminished by treatment with pertussis toxin. Phosphorylation of the mitogen-activated protein kinase (MAPK) isoforms, extracellular signal-regulated kinase 1 (ERK1) and ERK2, was increased in a CD4(+) CCR5(+) U87 cell line treated with AOP-RANTES or with an NSI/R5 HIV-1 isolate. These findings suggest that AOP-RANTES may induce a MAPK/ERK signal transduction pathway upon binding to a G-protein-coupled receptor. MAPK/ERK1 and -2 appear to phosphorylate the HIV-1 preintegration complex, a step necessary for nuclear translocation and successful integration.
 ...
PMID:Mechanisms involved in stimulation of human immunodeficiency virus type 1 replication by aminooxypentane RANTES. 1150 8

Infection with human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma (KS)-associated herpesvirus, is necessary for the development of KS. The HHV-8 lytic-phase gene ORF74 is related to G protein-coupled receptors, particularly interleukin-8 (IL-8) receptors. ORF74 activates the inositol phosphate/phospholipase C pathway and the downstream mitogen-activated protein kinases, JNK/SAPK and p38. We show here that ORF74 also activates NF-kappaB independent of ligand when expressed in KS-derived HHV-8-negative endothelial cells or primary vascular endothelial cells. NF-kappaB activation was enhanced by the chemokine GROalpha, but not by IL-8. Mutation of Val to Asp in the ORF74 second cytoplasmic loop did not affect ligand-independent signaling activity, but it greatly increased the response to GROalpha. ORF74 upregulated the expression of NF-kappaB-dependent inflammatory cytokines (RANTES, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor) and adhesion molecules (VCAM-1, ICAM-1, and E-selectin). Supernatants from transfected KS cells activated NF-kappaB signaling in untransfected cells and elicited the chemotaxis of monocytoid and T-lymphoid cells. Expression of ORF74 conferred on primary endothelial cells a morphology that was strikingly similar to that of spindle cells present in KS lesions. Taken together, these data, demonstrating that ORF74 activates NF-kappaB and induces the expression of proangiogenic and proinflammatory factors, suggest that expression of ORF74 in a minority of cells in KS lesions could influence uninfected cells or latently infected cells via autocrine and paracrine mechanisms, thereby contributing to KS pathogenesis.
 ...
PMID:Activation of NF-kappaB by the human herpesvirus 8 chemokine receptor ORF74: evidence for a paracrine model of Kaposi's sarcoma pathogenesis. 1150 11

Airway smooth muscle (ASM) is a potential source of multiple proinflammatory cytokines during airway inflammation. In the present study, we examined a requirement for mitogen-activated protein (MAP) kinase activation for interleukin (IL)-1beta-stimulated GM-CSF, RANTES, and eotaxin release. IL-1beta induced concentration-dependent phosphorylation of p42/p44 extracellular signal-regulated kinases (ERKs), p38 MAP kinase, and c-Jun amino-terminal kinase (SAPK/JNK). p42/p44 ERK and p38 MAP kinase phosphorylation peaked at 15 min and remained elevated up to 4 h. SAPK/JNK phosphorylation also peaked at 15 min but fell to baseline within 60 min. SB 203580 selectively inhibited IL-1beta-stimulated activation of p38 MAP kinase; U 0126 was selective against p42/p44 ERK activity. SB 202474, an inactive analog, had no effect on p42/p44 ERK, p38 MAP kinase, or SAPK/JNK activation, or on eotaxin or RANTES release. Eotaxin release was inhibited by SB 203580 and U 0126, whereas RANTES release was prevented by U 0126 only. GM-CSF release was inhibited by U 0126 but enhanced by SB 203580. These data indicate that RANTES release is dependent on p42/p44 ERK activation but occurs independently of p38 MAP kinase activity. Eotaxin release, however, is dependent on both p38 MAP kinase- and p42/p44 ERK-dependent mechanisms. GM-CSF release is p42/p44 ERK dependent and is tonically suppressed by a mechanism that is partially dependent on p38 MAP kinase, though direct inhibition of cyclooxygenase (COX) activity due to poor inhibitor selectivity may also contribute.
 ...
PMID:Inhibitors of mitogen-activated protein kinases differentially regulate eosinophil-activating cytokine release from human airway smooth muscle. 1152 Jul 38

The aim of this study was to learn more on the role of chemokines in the regulation of human megakryopoiesis. Normal human megakaryoblasts were expanded in serum-free liquid cultures and subsequently (1) phenotyped for expression of various chemokine receptors, (2) evaluated if chemokine receptors which they express are functional after stimulation by chemokines (calcium flux assay, chemotaxis, phosphorylation of MAPK-p42/44 and AKT proteins), and (3) investigated for expression and secretion of selected chemokines by employing RT-PCR and ELISA assays, respectively. In addition we also phenotyped peripheral blood platelets for expression of chemokine receptors and chemokines. We found that while human megakaryoblasts express several chemokine receptors (CXCR4, CCR6, CCR8, CCR5, CCR2 and CXCR3), CXCR4 was the only receptor detectable by FACS on human platelets. Moreover, among various chemokines tested, only SDF-1 (CXCR4 ligand) stimulated calcium flux and chemotaxis in normal human megakaryoblasts and phosphorylated MAPK-p42/44 and AKT in these cells. Although mRNAs for several chemokines were detectable by RT-PCR in normal human megakaryoblasts, only RANTES, IL-8, MCP-1 and PF-4 were found to be secreted by these cells. Finally we noticed that no chemokine tested in this study affected CFU-Meg colony formation by human CD34+ cells in serum-free cultures. We conclude that from all the chemokine receptor-chemokine axes tested, only SDF-1-CXCR4 axis was functional in assays employed in our studies, which further support the view that this axis plays a privileged role in regulating normal human megakaryopoiesis.
 ...
PMID:Biological significance of chemokine receptor expression by normal human megakaryoblasts. 1153 79

Rheumatoid arthritis (RA) is characterized by proliferation of synoviocytes that produce inflammatory cytokines and chemokines. The expressed chemokines are thought to be involved in the migration of inflammatory cells into the synovium. In this study we show that CCL2/monocyte chemotactic protein-1, CCL5/RANTES, and CXCL12/stromal cell-derived factor-1 enhanced IL-6 and IL-8 production by fibroblast-like synoviocytes (FLS) from patients with RA, and their corresponding receptors, CCR2, CCR5, and CXCR4, respectively, were expressed by RA FLS. The chemokines stimulated RA FLS more effectively than skin fibroblasts. Culture with CCL2 enhanced phosphorylation of extracellular signal-related kinase 1 (ERK1) and ERK2, but not phosphorylation of p38 or Src. Moreover, activation of ERK1/2 was inhibited by pertussis toxin, a G(i)-coupled protein inhibitor, and RS-504393, CCR2 antagonist, suggesting that ERK1/2 was activated by CCL2 via CCR2 and G(i)-coupled protein. On the other hand, CCL2, CCL5, and CXCL12 were expressed on RA FLS, and their production was regulated by TNF-alpha, IL-1beta, and TGF-beta1. Our results indicate that the chemokines not only play a role in inflammatory cell migration, but are also involved in the activation of FLS in RA synovium, possibly in an autocrine or paracrine manner.
 ...
PMID:Chemokines regulate IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with rheumatoid arthritis. 1167 56

We identified five human T-lymphoid cell lines (PB-1, Sez-4, C19PL, HUT 102B and ATL-2) which highly express CD4 in addition to CXCR4 and CCR5. In order to evaluate if these cells are infectabile by human immunodeficiency virus (HIV) and could be employed as a model in HIV research we exposed these cell lines to X4 (T-cell tropic) and R5 (macrophage tropic) and subsequently tried to correlate their infectability with (i) level of chemokine coreceptor (CXCR4 and CCR5) expression, (ii) coreceptor functionality (calcium flux, chemotaxis and phosphorylation of MAPK p42/44 and AKT) and (iii) endogenous expression and secretion of HIV-related chemokines which compete with the virus for binding to CXCR4 (SDF-1/CXCL12) or CCR5 (MIP-1beta/CCL4, MIP-1alpha/CCL3, RANTES/CCL5, MCP-2/CCL8, MCP-3/CCL7 and MCP-4/CCL13). We demonstrated that while PB-1 cells are infectable by both X4 and R5 HIV, Sez-4, C91PL, HUT 102B and ATL-2 cells were infected by X4 HIV only. Moreover, we noticed that the susceptibility of these cells to HIV did not correspond either with the level of surface expression or with the functionality of CXCR4 or CCR5; however, it was modulated to some degree by the endogenously secreted HIV-related chemokines. Thus all five mature T-cell lines described here may provide useful new models for studying various aspects of HIV infection. In addition we demonstrate that the infectability of cells by HIV is modulated by so far unidentified intrinsic factors as well as some already known endogenously secreted chemokines. The identification of these factors may be important for developing new strategies to protect cells from HIV infection.
 ...
PMID:New T-lymphocytic cell lines for studying cell infectability by human immunodeficiency virus. 1173 46

The interaction of the CC-chemokine RANTES with its cell surface receptors transduces multiple intracellular signals: low concentrations of RANTES (1 to 10 nM) stimulate G-protein-coupled receptor (GPCR) activity, and higher concentrations (1 microM) activate a phosphotyrosine kinase (PTK)-dependent pathway. Here, we show that the higher RANTES concentrations induce rapid tyrosine phosphorylation of multiple proteins. Several src-family kinases (Fyn, Hck, Src) are activated, as is the focal adhesion kinase p125 FAK and, eventually, members of the p44/p42 mitogen-activated protein kinase (MAPK) family. This PTK signaling pathway can be activated independently of known seven-transmembrane GPCRs for RANTES because it occurs in cells that lack any such RANTES receptors. Instead, activation of the PTK signaling pathway is dependent on the expression of glycosaminoglycans (GAGs) on the cell surface, in that it could not be activated by RANTES in GAG-deficient cells. We have previously demonstrated that RANTES can both enhance and inhibit infection of cells with human immunodeficiency virus type 1 (HIV-1). Here we show that activation of both PTK and MAPK is involved in the enhancement of HIV-1 infectivity caused by RANTES in cells that lack GPCRs for RANTES but which express GAGs.
 ...
PMID:Interaction of the CC-chemokine RANTES with glycosaminoglycans activates a p44/p42 mitogen-activated protein kinase-dependent signaling pathway and enhances human immunodeficiency virus type 1 infectivity. 1183 2

Activating cells of the immune system may stimulate human immunodeficiency virus type 1 (HIV-1) replication and contribute to select pathogenic variants in vivo. Here, we examined the possible effect of a major pathway of immune activation, CD40 interaction with its ligand (CD40L), on the susceptibility of monocyte-derived macrophages (MDMs) to various HIV-1 strains. Stimulation of MDMs with CD40L led to reduced replication of R5 HIV-1(Ba-L), whereas this strongly enhanced the replication of X4 HIV-1(Lai) as well as of X4 primary isolates, and this was associated with strong cytopathic effects. The replication of X4 strains was inhibited by stromal cell-derived factor 1, an indication of the restricted usage of CXCR4 as virus coreceptor in this case. CD40L induced the activation of mitogen-activated protein kinases ERK1/ERK2 and stimulated MDMs to secrete RANTES (regulated on activation, normal T cell expressed and secreted), macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, interleukin 6 (IL-6), IL-1beta, and tumor necrosis factor alpha. From this data, it may be hypothesized that activated macrophages represent a favorable environment for the replication of classically T lymphocyte-tropic X4 variants and, thus, may contribute significantly to the selection of such variants at late stages of clinical HIV-1 infection.
 ...
PMID:CD40-activated macrophages become highly susceptible to X4 strains of human immunodeficiency virus type 1. 1183 43

RANTES (regulated on activation normal T cell expressed and secreted) (> or =10 ng/ml) stimulates the induction of KC and other chemokines in astrocytes. Elements of the signal transduction pathway controlling this response were identified. RANTES induced phosphorylation of MEK, ERK1/2, p90 ribosomal S6 kinases (RSK), and cAMP-response element-binding protein (CREB) in astrocytes. U0126, a pharmacological inhibitor of MEK, blocked the phosphorylation of the downstream elements ERK, RSK, and CREB, inhibited chemokine synthesis, and reduced transcription from a KC promoter construct. Dominant negative mutants of RSK or CREB blocked the transcription driven by the KC promoter. Finally, RANTES treatment induces nuclear translocation of phosphorylated RSK in astrocytes. This novel role for RSK in signaling chemokine responses and synthesis in astrocytes may contribute to the amplification mechanisms responsible for prolonging inflammatory responses in the central nervous system.
 ...
PMID:RANTES-mediated chemokine transcription in astrocytes involves activation and translocation of p90 ribosomal S6 protein kinase (RSK). 1189 39


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