Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophages are major targets for infection by human immunodeficiency virus type 1 (HIV-1). In addition to their role as productive viral reservoirs, inappropriate activation of infected and uninfected macrophages appears to contribute to pathogenesis. HIV-1 infection requires initial interactions between the viral envelope surface glycoprotein gp120, the cell-surface protein CD4, and a chemokine receptor CCR5 or CXCR4. Besides their role in HIV-1 entry, CCR5 and CXCR4 are G protein-coupled receptors that can activate multiple intracellular signaling pathways. HIV-1 gp120 has been shown to activate signaling pathways through the chemokine receptors in several cell types including lymphocytes, neurons, and astrocytes. In some cell types, these consequences may cause cellular injury. In this review, we highlight our data demonstrating diverse signaling events that occur in primary human macrophages in response to gp120/chemokine receptor interactions. These responses include K+, Cl-, and nonselective cation currents, intracellular Ca2+ increases, and activation of several kinases including the focal adhesion-related tyrosine kinase Pyk2, mitogen-activated protein kinases (MAPK), and phosphoinositol-3 kinase. Activation of the MAPK leads to gp120-induced expression of chemokines such as monocyte chemoattractant protein-1 and macrophage-inflammatory protein-1beta and the proinflammatory cytokine tumor necrosis factor alpha. These responses establish a complex cytokine network, which may enhance or suppress HIV-1 replication. In addition, dysregulation of macrophage function by gp120/chemokine receptor signaling may contribute to local inflammation and injury and further recruit additional inflammatory and/or target cells. Targeting these cellular signaling pathways may have benefit in controlling inflammatory sequelae of HIV infection such as in neurological disease.
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PMID:Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signaling pathways. 1296 Feb 31

Among the various chemokines that are functionally active on neutrophils, platelet factor 4 (PF-4; CXCL4) appears to have a specialized role. Lacking typical chemokine activities, PF-4 stimulates neutrophils to undergo firm adhesion to endothelial cells and, in the presence of an appropriate costimulus like tumor necrosis factor (TNF), PF-4 induces exocytosis of secondary granule contents. Analyzing the individual contribution of PF-4 and its costimuli in the control of these functions at the signaling level, we demonstrate that TNF-induced activation of p38 mitogen-activated protein (MAP) kinase (but not extracellular regulated kinase [Erk] kinases) acts as general and essential costimulatory signal in PF-4-dependent neutrophil exocytosis. This was shown by the use of a specific inhibitor (SB203580), by biologic (lipopolysaccharide, N-formyl-methionyl-leucyl-phenylalanine) and pharmacologic (anisomycin) activators of p38 MAP kinase, and by phosphorylation studies. Furthermore, TNF-mediated activation of phosphatidylinositol 3-kinase (PI 3-kinase) represents an additional essential signaling component in this process as demonstrated by studies with its inhibitor wortmannin as well as by analysis of the phosphorylation of AKT kinase. PF-4, however, directly activates src-kinases and PF-4-induced adherence as well as PF-4/TNF-mediated exocytosis was inhibited by an src-kinase inhibitor PP1. Taken together, neutrophil exocytosis and adherence are regulated on p38 MAP kinase, PI 3-kinase, and src-kinase activation.
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PMID:Platelet factor 4 (PF-4)-induced neutrophil adhesion is controlled by src-kinases, whereas PF-4-mediated exocytosis requires the additional activation of p38 MAP kinase and phosphatidylinositol 3-kinase. 1459 23

The interaction between CD40 ligand (CD154) expressed on activated T cells and its receptor, CD40, has been shown to play a role in the onset and maintenance of autoimmune inflammation. Recent studies suggest that CD154+T cells also contribute to the regulation of atherogenesis due to their capacity to activate CD40+cells of the vasculature, including vascular smooth muscle cells (VSMC). The present study evaluated the signalling events initiated through CD40 ligation which culminate in VSMC chemokine production. CD40 ligation resulted in the phosphorylation/activation of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and p38, but not c-jun N-terminal kinase. Inhibition of both ERK1/2 and p38 activity abrogated CD40 stimulation of IL-8 and MCP-1 production. CD40-mediated induction of chemokines also showed dependence on the Src family kinase activity. The Src kinase inhibitor, PP2, was found to inhibit CD40-induced phosphorylation of ERK1/2 as well as activation of IkappaB kinase. An evaluation of Src kinases that may be important in CD40 signalling identified Lyn as a potential candidate. These data indicate that CD40 signalling in VSMC activates a Src family kinase-initiated pathway that results in the induction of MAPK activities required for successful induction of chemokine synthesis.
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PMID:CD40-mediated activation of vascular smooth muscle cell chemokine production through a Src-initiated, MAPK-dependent pathway. 1468 67

Human immunodeficiency virus type 1 (HIV-1) uses the chemokine receptors CCR5 and CXCR4 for entry. Macrophages and microglia (M/M) are the principal productively infected brain cells in HIV encephalopathy (HIVE), and neuronal injury is believed to result both from direct effects of viral proteins and indirect effects mediated by macrophage activation and secretion of neurotoxic products. In vitro, direct injury by the viral envelope glycoprotein gp120 can be mediated by neuronal CXCR4, but most HIV-1 isolates from the central nervous system (CNS) studied to date use CCR5 (R5 strains) rather than CXCR4 (X4 or R5X4 strains). Additionally, it remains unknown how HIV induces M/M activation and neurotoxin secretion. To address these issues, the authors analyzed a CNS-derived primary isolate, TYBE, and showed that it uses CXCR4 only and replicates efficiently in macrophages through CXCR4-mediated entry. The authors also showed that both R5 and X4 gp120 activate intracellular signals in macrophages through CCR5 and CXCR4, including calcium elevations; K+, Cl- and nonselective cation channel activation; phosphorylation of the nonreceptor tyrosine kinase Pyk2; and activation of p38 and SAPK/JNK mitogen-activated protein kinases (MAPKs). Finally, the authors showed that macrophages stimulated with gp120 produce soluble factors through MAPK-dependent pathways, including beta-chemokines implicated in HIVE pathogenesis. The findings emphasize that both X4 and R5 HIV-1 isolates may contribute to HIVE pathogenesis, and that gp120/chemokine receptor interactions in M/M trigger specific signal transduction pathways that may affect M/M function and provide a mechanism underlying CNS injury.
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PMID:Chemokine receptor utilization and macrophage signaling by human immunodeficiency virus type 1 gp120: Implications for neuropathogenesis. 1498 45

LL-37 is a cationic peptide that is found in the granules of neutrophils and is secreted by epithelial cells from a variety of tissues. Levels of LL-37 in vivo increase upon infection, and its production and secretion are increased upon stimulation with proinflammatory mediators. It has been postulated that LL-37 modulates the immune response by interacting with the effector cells of innate immunity; however, the mechanism of this interaction is unknown. LL-37 induced phosphorylation and activation of the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) and p38, in human peripheral blood-derived monocytes and a human bronchial epithelial cell line, but not in B or T lymphocytes. Phosphorylation was not dependent on the G protein-coupled formyl peptide-like receptor 1, which was previously proposed to be the receptor for LL-37-induced chemotaxis on human monocytes and T cells. Activation of ERK1/2 and p38 was markedly increased by the presence of GM-CSF, but not M-CSF. Exposure to LL-37 also led to the activation of Elk-1, a transcription factor that is downstream of and activated by phosphorylated ERK1/2, the up-regulation of various Elk-1-controlled genes, and the transcription and secretion of IL-8. Inhibition of either p38 or ERK1/2 kinases led to a reduction in LL-37-induced IL-8 secretion and inhibition of the transcription of various chemokine genes. The ability of LL-37 to signal through these pathways has broad implications in immunity, monocyte activation, proliferation, and differentiation.
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PMID:The human cationic peptide LL-37 induces activation of the extracellular signal-regulated kinase and p38 kinase pathways in primary human monocytes. 1500 80

Infection of epithelial cells by the microbial pathogen Helicobacter pylori leads to activation of the transcription factor nuclear factor kappaB (NF-kappaB), the induction of pro-inflammatory cytokine/chemokine genes, and the motogenic response (cell scattering). Here we report that H. pylori-induced NF-kappaB activation and the subsequent release of interleukin 8 (IL-8) are inhibited by curcumin (diferuloylmethane), a yellow pigment in turmeric (Curcuma longa L.). Our results demonstrate that curcumin inhibits IkappaBalpha degradation, the activity of IkappaB kinases alpha and beta (IKKalpha and beta), and NF-kappaB DNA-binding. The mitogen-activated protein kinases (MAPK), extracellular signal-regulated kinases 1/2 (ERK1/2) and p38, which are also activated by H. pylori infection, were not inhibited by curcumin. Further, the H. pylori-induced motogenic response was blocked by curcumin. We conclude that curcumin, due to inhibition of NF-kappaB activation and cell scattering, should be considered as a potential therapeutic agent effective against pathogenic processes initiated by H. pylori infection.
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PMID:Curcumin blocks NF-kappaB and the motogenic response in Helicobacter pylori-infected epithelial cells. 1504 93

Allergic asthma and allergic rhinitis are inflammatory diseases of the airway. Cytokines and chemokines produced by T helper (Th) type 2 cells (GM-CSF, IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13), eotaxin, transforming growth factor-beta, and IL-11 orchestrate most pathophysiological processes of the late-phase allergic reaction, including the recruitment, activation, and delayed apoptosis of eosinophils, as well as eosinophilic degranulation to release eosinophilic cationic protein, major basic protein, and eosinophil-derived neurotoxin. These processes are regulated through an extensive network of interactive intracellular signal transduction pathways that have been intensively investigated recently. Our present review updates the cytokine and chemokine-mediated signal transduction mechanisms including the RAS-RAF-mitogen-activated protein kinases, Janus kinases (signal transducers and activators of transcription), phosphatidylinositol 3-kinase, nuclear factor-kappa B, activator protein-1, GATA, and cyclic AMP-dependent pathways, and describes the roles of different signaling pathways in the regulation of eosinophil differentiation, recruitment, degranulation, and expression of adhesion molecules. We shall also discuss different biochemical methods for the assessment of various intracellular signal transduction molecules, and various antagonists of receptors, modulators, and inhibitors of intracellular signaling molecules, many of which are potential therapeutic agents for treating allergic diseases.
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PMID:Biochemical assessment of intracellular signal transduction pathways in eosinophils: implications for pharmacotherapy. 1507 24

The role of chemokines and their receptors in HIV biology and Kaposi's sarcoma (KS) pathogenesis has recently gained considerable attention. It has been shown that KS-associated human herpes virus type 8 (KSHV/HHV-8) encodes functional homologues of certain chemokines and chemokine receptors. This suggests that chemokines may contribute to the growth and spread of KS seen in AIDS. We found the expression of CXCR4 in primary KS tissue by using in situ hybridization (ISH). Recently, alpha-chemokine receptors CXCR1 and CXCR2 have also been shown to be expressed by KS tissues. We further characterized the expression of these chemokines as well as the signaling events induced upon binding to their respective cognate ligands in the KS 38 spindle cell line. These cells express authentic characteristics of primary KS spindle cells and provide a useful in vitro model for these studies. We observed using RT-PCR that KS 38 cells express mRNA for the alpha-chemokine receptors CXCR1, CXCR2, and CXCR4. We also confirmed the cell surface protein expression by FACS analysis. Characterization of signaling pathways revealed that the alpha-chemokines, IL-8 and stromal cell-derived factor 1alpha (SDF1alpha/CXCL12), activated members of the mitogen-activated protein (MAP) kinase family, including Erk kinase, c-Jun amino terminal kinase (JNK)/stress-activated protein kinase (SAPK) and the p38 MAP kinase. Furthermore, using DNA protein-binding experiments, we have shown that IL-8 increased AP-1 and NF Kappa B activity in these cells. IL-8 also enhanced the chemotaxis of KS cells. These results reveal that chemokine-induced signaling pathways may mediate cell growth, transcriptional activation and cell migration in KS.
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PMID:Alpha-chemokine-mediated signal transduction in human Kaposi's sarcoma spindle cells. 1511 Sep 93

Antagonism of chemokines on chemokine receptors constitutes a new regulatory principle in inflammation. Eotaxin (CCL11), an agonist for CCR3 and an attractant of eosinophils, basophils, and Th2 lymphocytes, was shown to act as an antagonist for CCR2, which is widely expressed on leukocytes and is essential for inflammatory responses. In this report we provide direct evidence for a novel mechanism how chemokine receptor function can be arrested by endogenous ligands. We show that binding of eotaxin to CCR2 stimulates the mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 (ERK1/2). Activation of the mitogen-activated protein kinase kinase 1/2-ERK pathway is indispensable for eotaxin-mediated attenuation of CCR2 function, as inhibition of ERK phosphorylation abolishes the arresting effect. ERK is also activated by CCR2 agonists, e.g., monocyte chemoattractant protein-1 (CCL2). However, the involved pathways are different, although in either case coupling of CCR2 to pertussis toxin-sensitive heterotrimeric G proteins is necessary. The results are in agreement with the view that CCR2 could assume different activation states depending on the ligand it encounters. With respect to actin polymerization and calcium mobilization, the different activation states lead to agonistic and antagonistic responses. It is conceivable that the intracellular signal transduction pathway that is activated by eotaxin could cause an attenuation of proinflammatory responses mediated by CCR2.
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PMID:Unusual chemokine receptor antagonism involving a mitogen-activated protein kinase pathway. 1515 88

Classical chemoattractants such as fMLP or the complement factor C5a use G protein (Gi)-coupled receptors to stimulate both chemotaxis and production of reactive oxygen species (respiratory burst, RB) by polymorphonuclear leukocytes (PMN). The chemokine stroma cell-derived factor 1alpha (SDF1alpha) and its Gi-coupled receptor, CXCR4, regulate leukocyte trafficking and recruitment to the synovial fluid of rheumatoid arthritic patients (RA-SF). However, the role of SDF1alpha in the RB is unknown and was studied in this work in vitro with healthy PMN in the absence and presence of RA-SF. In healthy PMN, SDF1alpha failed to stimulate the RB, even though the p38 mitogen-activated protein kinase was activated to a similar level as in fMLP-stimulated PMN. In contrast, the SDF1alpha-mediated calcium transients and activation of phosphatidylinositol 3-kinase/Akt were partially deficient, while p44/42 mitogen-activated protein kinases were not activated. SDF1alpha actually desensitized weakly the fMLP-mediated RB of healthy PMN. This cross-inhibitory effect was amplified in PMN treated with RA-SF, providing a protection against the exacerbation of RB induced by C5a or fMLP. This SDF1alpha beneficial effect, which was prevented by the CXCR4 antagonist AMD3100, was associated with impairment of C5a- and fMLP-mediated early signaling events. Thus, although SDF1alpha promotes leukocyte emigration into rheumatoid synovium, our data suggest it cross-desensitizes the production of oxidant by primed PMN, a property that may be beneficial in the context of arthritis.
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PMID:Stroma cell-derived factor 1alpha mediates desensitization of human neutrophil respiratory burst in synovial fluid from rheumatoid arthritic patients. 1515 37


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