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: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leukocyte recruitment is a key step in the inflammatory reaction. Several changes in the cell morphology take place during lymphocyte activation and migration: spheric-shaped resting T cells become polarized during activation, developing a well defined cytoplasmic projection designated as cellular uropod. We found that the chemotactic and proinflammatory chemokines RANTES, MCP-1, and, to a lower extent, MIP-1 alpha, MIP-1 beta, and IL-8, were able to induce uropod formation and ICAM-3 redistribution in T lymphoblasts adhered to ICAM-1 or VCAM-1. A similar chemokine-mediated effect was observed during T cells binding to the fibronectin fragments of 38- and 80-kD, that contain the binding sites for the integrins VLA-4 and VLA-5, respectively. The uropod structure concentrated the ICAM-3 adhesion molecule (a ligand for LFA-1), and emerged to the outer milieu from the area of contact between lymphocyte and protein ligands. In addition, we found that other adhesion molecules such as ICAM-1, CD43, and CD44, also redistributed to the lymphocyte uropod upon RANTES stimulation, whereas a wide number of other cell surface receptors did not redistribute. Chemokines displayed a selective effect among different T cell subsets; MIP-1 beta had more potent action on CD8+ T cells and tumor infiltrating lymphocytes (TIL), whereas RANTES and MIP-1 alpha targeted selectively CD4+ T cells. We have also examined the involvement of cAMP signaling pathway in uropod formation. Interestingly, several cAMP agonists were able to induce uropod formation and ICAM-3 redistribution, whereas H-89, a specific inhibitor of the cAMP-dependent protein kinase, abrogated the chemokine-mediated uropod formation, thus pointing out a role for cAMP-dependent signaling in the development of this cytoplasmic projection. Since the lymphocyte uropod induced by chemokines was completely abrogated by Bordetella pertussis toxin, the formation of this membrane projection appears to be dependent on G proteins signaling pathways. In addition, the involvement of myosin-based cytoskeleton in uropod formation and ICAM-3 redistribution in response to chemokines was suggested by the prevention of this phenomenon with the myosin-disrupting agent butanedione monoxime. Interestingly, this agent also inhibited the ICAM-3-mediated cell aggregation, but not the cell adhesion to substrata. Altogether, these results demonstrate that uropod formation and adhesion receptor redistribution is a novel function mediated by chemokines; this phenomenon may represent a mechanism that significantly contributes to the recruitment of circulating leukocytes to inflammatory foci.
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PMID:Chemokines regulate cellular polarization and adhesion receptor redistribution during lymphocyte interaction with endothelium and extracellular matrix. Involvement of cAMP signaling pathway. 759 74

The adherence and transmigration of T cells through microvascular endothelium is an essential step for recruitment into inflammatory lesions, although the factors that stimulate the directional migration of T cells have not been fully characterized. In the present study we investigated the capacity of chemokines to induce migration of T cells across dermal microvascular endothelial cell monolayer. The results showed that recombinant MCP-1 significantly induced transendothelial migration of both resting and activated T cells. Maximal induction of migration was observed at a concentration of 10 ng/ml and a 3- to 4-hr incubation period. In contrast, the chemokines IL-8, RANTES, and MIP-1 alpha failed to stimulate T cell migration at doses as high as 100 ng/ml. In studies designed to investigate the intracellular signaling pathways mediating the MCP-1 effect, the results showed that MCP-1 at doses ranging from 10 to 100 ng/ml did not cause an increase in intracellular calcium ions in T cells, even though this chemokine induced rapid calcium mobilization in monocytes. Furthermore, pretreatment of T cells with either bisindolymaleimide HCl, a specific inhibitor of protein kinase C, or genistein, a protein tyrosine kinase inhibitor, significantly decreased the MCP-1-induced transmigration in a dose-dependent manner. In contrast, T cells pretreated with the protein kinase A-specific inhibitor H89 responded normally to MCP-1 stimulation. Finally, T cell transmigration was inhibited by antibodies against CD11a, thereby confirming the importance of beta 2-integrin in the transmigration process.
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PMID:The intracellular signaling pathways involved in MCP-1-stimulated T cell migration across microvascular endothelium. 860 36

In this report we characterize the induction mechanisms of two chemokine genes, MuRantes and crg-2, the murine homologs of human RANTES and IP-10, respectively, in primary rat astrocytes and microglia by the neurotropic paramyxovirus, Newcastle Disease Virus (NDV). The time course for NDV induction of both MuRantes and crg-2 genes in astrocytes and microglia was similar, with peak mRNA expression at 10-12 h. Unlike crg-2, MuRantes mRNA was not induced by IFN-gamma. MuRantes and crg-2 are transcriptionally induced by noninfectious, UV-irradiated NDV in astrocytes and microglia, unlike TNFalpha gene transcription, which is induced only by live NDV. These data indicate that signals generated through virus-receptor interaction on the target cell surface suffice to initiate MuRantes and crg-2 gene transcription in the absence of viral replication. In astrocytes, MuRantes mRNA accumulation in response to NDV was completely blocked by tyrosine kinase inhibitors, and partially by PKC and PKA inhibitors, whereas crg-2 mRNA accumulation was significantly inhibited by PKC inhibitors, but minimally or not affected by inhibitors of tyrosine kinase or PKA activity. These kinase inhibitors also affected MuRantes and crg-2 gene transcription in similar patterns to those observed for mRNA levels, but did not reduce the mRNA stability. Therefore, the signals required for mRNA accumulation appear to operate at the level of transcription. Efficient transcription of MuRantes and crg-2 genes may require different sets of transcriptional proteins and enhancers that are regulated by different signaling pathways activated by NDV.
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PMID:Regulatory mechanisms of MuRantes and CRG-2 chemokine gene induction in central nervous system glial cells by virus. 890 50

Pseudomonas aeruginosa, an opportunistic human pathogen, causes acute pneumonia in patients with hospital-acquired infections and is commonly associated with chronic lung disease in individuals with cystic fibrosis (CF). Evidence suggests that the pathophysiological effects of P. aeruginosa are mediated in part by virulence factors secreted by the bacterium. Among these factors is pyocyanin, a redox active compound that increases intracellular oxidant stress. We find that pyocyanin increases release of interleukin-8 (IL-8) by both normal and CF airway epithelial cell lines and by primary airway epithelial cells. Moreover, pyocyanin synergizes with the inflammatory cytokines tumor necrosis factor alpha and IL-1alpha. RNase protection assays indicate that increased IL-8 release is accompanied by increased levels of IL-8 mRNA. The antioxidant n-acetyl cysteine, general inhibitors of protein tyrosine kinases, and specific inhibitors of mitogen-activated protein kinases diminish pyocyanin-dependent increases in IL-8 release. Conversely, inhibitors of protein kinases C (PKC) and PKA have no effect. In contrast to its effects on IL-8 expression, pyocyanin inhibits cytokine-dependent expression of the monocyte/macrophage/T-cell chemokine RANTES. Increased release of IL-8, a potent neutrophil chemoattractant, in response to pyocyanin could contribute to the marked infiltration of neutrophils and subsequent neutrophil-mediated tissue damage that are observed in Pseudomonas-associated lung disease.
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PMID:Pseudomonas pyocyanin increases interleukin-8 expression by human airway epithelial cells. 982 54

The HIV-1 envelope protein gp120 induces apoptosis in hippocampal neurons. Because chemokine receptors act as cellular receptors for HIV-1, we examined rat hippocampal neurons for the presence of functional chemokine receptors. Fura-2-based Ca imaging showed that numerous chemokines, including SDF-1alpha, RANTES, and fractalkine, affect neuronal Ca signaling, suggesting that hippocampal neurons possess a wide variety of chemokine receptors. Chemokines also blocked the frequency of spontaneous glutamatergic excitatory postsynaptic currents recorded from these neurons and reduced voltage-dependent Ca currents in the same neurons. Reverse transcription-PCR demonstrated the expression of CCR1, CCR4, CCR5, CCR9/10, CXCR2, CXCR4, and CX3CR1, as well as the chemokine fractalkine in these neurons. Both fractalkine and macrophage-derived chemokine (MDC) produced a time-dependent activation of extracellular response kinases (ERK)-1/2, whereas no activation of c-JUN NH2-terminal protein kinase (JNK)/stress-activated protein kinase, or p38 was evident. Furthermore, these two chemokines, as well as SDF-1alpha, activated the Ca- and cAMP-dependent transcription factor CREB. Several chemokines were able also to block gp120-induced apoptosis of hippocampal neurons, both in the presence and absence of the glial feeder layer. These data suggest that chemokine receptors may directly mediate gp120 neurotoxicity.
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PMID:Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity. 982 29

Several recent studies have provided clear evidence that angiotensin-converting enzyme (ACE)-inhibitors slow the progression of renal disease. These effects are mainly independent from a comitant reduction in systemic blood pressure. Thus, angiotensin II (Ang II) exerts other effects on the kidney which are involved in the loss of renal function. Ang II induces proliferation of cultured mesangial and glomerular endothelial cells. Our group was the first to demonstrate that Ang II stimulates hypertrophy of cultured proximal tubular cells. Ang II stimulates bioactivation and expression of transforming growth factor-beta (TGF-beta) in tubular MCT cells. This Ang II-mediated expression of TGF-beta is due to an increase in transcriptional activity. A neutralizing anti-TGF-beta antibody attenuates the Ang II-induced increase in protein synthesis in MCT cells suggesting that the hypertrophy is mediated by synthesis and activation of endogenous TGF-beta. Proximal tubular cells undergoing Ang II-mediated hypertrophy are arrested in the G1-phase of the cell cycle and express typical G1-phase-associated genes. Induction of such G1-phase-associated early growth response genes have been also described in vivo after infusion of Ang II into the renal artery. This G1-phase arrest depends on the induction of the cyclin-dependent kinase (CdK) inhibitor p27Kip1. p27Kip1 expression is stimulated after incubation of LLC-PK1 cells with Ang II or TGF-beta and binds to cyclin D1-CdK4 complexes, inhibits their kinase activity, and hampers G1-phase exit. Ang II stimulates transcription of collagen type IV in MCT cells. In addition to the classical a1 (IV) chain, a3 (IV) collagen, which has normally a restricted localization in the kidney, is also induced. This stimulation is mediated by endogenous synthesis and autocrine action of TGF-beta because a neutralizing anti-TGF-beta antibody as well as TGF-beta antisense oligonucleotides attenuate Ang II-induced collagen type IV transcription and synthesis. In addition, Ang II exerts immunomodulatory effects on the kidney through the induction of chemokines such as MCP-1 and RANTES. In conclusion, Ang II has emerged as a multifunctional acting as a growth factor and a profibrogenic cytokine, and even having inflammatory properties.
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PMID:Angiotensin II is involved in the progression of renal disease: importance of non-hemodynamic mechanisms. 985 83

The intracellular signaling pathways involved in human monocyte chemotaxis toward a variety of chemoattractant molecules were evaluated using selected pharmacological agents. Neither phosphatidylinositol-3-kinase (P13K) or extracellular signal-regulated kinase (ERK) activity were required for monocyte migration toward monocyte chemoattractant protein-1 (MCP-1), RANTES (Regulated on Activation, Normal T cell Expressed and Secreted), macrophage inflammatory protein-1alpha (MIP-1alpha) or formyl-Met-Leu-Phe (fMLP), since pretreatment with wortmannin or LY294002, or with PD098059, had no effect on the chemotactic response. Addition of forskolin and IBMX significantly attenuated chemotaxis to each of these chemoattractants and was reversed by co-treatment with Rp-cAMP, a competitive inhibitor of cAMP-dependent protein kinase A. Incubation with the protein kinase C (PKC) inhibitor GF109203X-HCl (GF109) did not affect monocyte migration, but pretreatment of monocytes with PMA significantly impaired the response to each of these chemotactic agents. Inhibition by PMA was reversed by co-treatment with GF109, implying that heterologous PKC activation is capable of desensitizing chemokine and fMLP-induced monocyte chemotaxis. These results help to define the signalling pathways involved in human monocyte chemotaxis and suggest pharmacological approaches to evaluating the cross-desensitization of chemoattractant-induced leukocyte migration.
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PMID:Evaluation of signal transduction pathways in chemoattractant-induced human monocyte chemotaxis. 1132 60

Emedastine difumarate (emedastine) is an antiallergic drug found among the derivatives which has a series of benzimidazole frames. It has been reported that emedastine can significantly inhibit the migration of eosinophils elicited by classical chemoattractants, including LTB4 or PAF. However, the effect of emedastine on the selective migration of eosinophils that have been stimulated with CC chemokines has not been examined. Emedastine at concentrations of 10 nM or higher strongly inhibited the eosinophil migration elicited by CC chemokines, including eotaxin, RANTES and MCP-3. Preincubation of the eosinophils with emedastine did not alter the expression of the CCR3 receptor, although a decrease in the concentration of intracellular calcium ions was observed after stimulation with 100 ng/ml of eotaxin. Herbimycin A, genistein, staurosporin and emedastine were all able to inhibit the eotaxin-elicited migration. Tyrosine kinase activity in the cytosol supernatant of eosinophils obtained after stimulation with eotaxin significantly decreased when the eosinophils were preincubated with emedastine. In addition, protein kinase A and protein kinase C activities in eotaxin-stimulated EoL-1 cell supernatants decreased significantly with emedastine pretreatment. These findings suggest that emedastine inhibits CC chemokine-elicited eosinophil migration by decreasing the activities of tyrosine kinase or protein kinases but does not alter CCR3 expression.
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PMID:Effect of emedastine difumarate on CC chemokine-elicited eosinophil migration. 1140 68

Recruitment of leukocytes is essential for eventual control of virus infections. Macrophages represent a leukocyte population involved in the first line of defense against many infections, including herpes simplex virus (HSV) infection. Through presentation of antigens to T cells and production of cytokines and chemokines, macrophages also constitute an important link between the innate and adaptive immune systems. Here, we have investigated the chemokine expression profile of macrophages after HSV infection and the virus-cell interactions involved. By reverse transcription-PCR and cDNA arrays, we found that HSV type 1 (HSV-1) and HSV-2 induced expression of the CC chemokine RANTES/CCL5 in murine macrophage cell lines and peritoneal cells. The CXC chemokine BCA-1/CXCL13 was also induced in peritoneal cells. Twenty-six other chemokines tested were not affected. Accumulation of RANTES mRNA was detectable after 5 h of infection, was sensitive to UV irradiation of the virus, and was preceded by accumulation of viral immediate-early mRNA and proteins. The viral components responsible for initiation of RANTES expression were examined with virus mutants and RAW 264.7 macrophage-like cells expressing a dominant negative mutant of the double-stranded-RNA-activated protein kinase (PKR). The PKR mutant cell line displayed reduced constitutive and HSV-inducible RANTES expression compared to the control cell line. HSV-1 mutants deficient in genes encoding the immediate-early proteins ICP4, ICP22, and ICP27 remained fully capable of inducing RANTES expression in macrophages. By contrast, the ability of an ICP0-deficient HSV-1 mutant to induce RANTES expression was compromised. Thus, HSV selectively induces expression of RANTES in macrophages through a mechanism dependent on cellular PKR and viral ICP0.
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PMID:Herpes simplex virus selectively induces expression of the CC chemokine RANTES/CCL5 in macrophages through a mechanism dependent on PKR and ICP0. 1186 45

The chemokine RANTES (regulated on activation normal T cell expressed and secreted) is expressed in several inflammatory diseases of the central nervous system and is a powerful stimulus for astrocyte production of proinflammatory mediators. The mechanism of RANTES-mediated astrocyte activation was investigated. RANTES stimulation decreased both intracellular cyclic AMP (cAMP) levels and cAMP-dependent protein kinase A (PKA) activity in cultures of primary mouse astrocytes. H-89, a potent inhibitor of PKA, mimicked RANTES-mediated chemokine and cytokine transcription. RANTES treatments activated Raf-1 kinase activity, and conversely a dominant negative Raf and a Raf-1 inhibitor blocked RANTES-induced chemokine transcription. Transfection with a constitutively active Raf was sufficient to induce transcription of proinflammatory mediators. The combined data indicate that Raf-1 is required for RANTES-mediated astrocyte activation. Decreases of cAMP and PKA activity contributed to the transcription of proinflammatory mediators by cross-talk with the Raf-1/mitogen-activated protein kinase pathway. The results identify an upstream signaling pathway for amplification of proinflammatory mediators in the central nervous system.
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PMID:Negative role of cAMP-dependent protein kinase A in RANTES-mediated transcription of proinflammatory mediators through Raf. 1258 31


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