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)

We have identified three anti-murine LFA-1 alpha monoclonal antibodies (M17/4.2, G-48, and FD441.8) which are capable of inducing homotypic aggregation of murine T cell lines (3A9 EL-4 cells). The LFA-1-induced aggregation is temperature-dependent, necessitates metabolic energy, and requires an intact cytoskeleton, but is independent of transcription and protein synthesis. The aggregation is inhibited in Ca2+ and Mg2+ free media and is also blocked with EDTA and EGTA. The aggregation does not involve protein kinase A or C or changes in intracellular calcium. The LFA-1 alpha-induced homotypic aggregation is inhibited with LFA-1 beta antibodies, but not with antibodies targeting ICAM-1, VCAM-1, VLA-4, or CD2. 3A9 cells do not express the LFA-1 ligand ICAM-1, whereas EL-4 cells express moderate amounts of ICAM-1. Thus, targeting LFA-1 alpha with mAb results in homotypic aggregation of T cell lines which is independent of ICAM-1/LFA-1 interactions, but may involve other LFA-1 ligands such as ICAM-2 or ICAM-3. Alternatively, LFA-1 may function as a signaling molecule, triggering other yet to be defined adhesion molecules to interact.
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PMID:Monoclonal antibodies targeting murine LFA-1 induce LFA-1/ICAM-1-independent homotypic lymphocyte aggregation. 135 33

The fate of E-selectin expressed on TNF-activated monolayers of HUVEC was investigated by confocal laser scanning microscopy. Cytokine-activated endothelial cells internalized mAb to E-selectin in a very rapid, energy-dependent fashion. By contrast, mAb against ICAM-1 and VCAM-1 remained surface bound. The E-selectin mAb was recovered in intracellular compartments with a tubular morphology, some of which appeared to be interconnected. Cathepsin B, a ubiquitously expressed lysosomal protease, was found to co-localize in these structures. Functional specificity of E-selectin-internalization was observed upon addition of the fluorescent SLex-oligosaccharide to the activated HUVEC monolayers. Uptake into the same E-selectin-positive compartments was observed, whereas the control oligosaccharide Lex was not internalized at all. The process of internalization was found to be unaffected by most inhibitors of protein kinase C, cAMP-dependent PKA, or protein tyrosine kinase activity. Whereas cytochalasin B preincubation of HUVEC failed to inhibit the internalization process, colchicine and vinblastine, reagents that interfere with the metabolism of tubulin, prevented the formation of the elongated structures in which E-selectin would normally be internalized. Concomitantly, the expression of E-selectin at the cell surface was significantly increased.
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PMID:Cytokine-activated endothelial cells internalize E-selectin into a lysosomal compartment of vesiculotubular shape. A tubulin-driven process. 751 27

Cytokines induce the expression of E-selectin, VCAM-1, and ICAM-1 on human umbilical vein endothelial cells (HUVECs). We show that expression of these surface proteins is differently affected by cAMP. Increased cAMP levels decrease E-selectin and VCAM-1 but increase ICAM-1 expression. We demonstrate by mRNA half-life analysis and nuclear run-on assays that the cAMP repression of E-selectin occurs at the transcription level. This effect is abolished by protein kinase A inhibition, suggesting that repression is mediated by protein kinase A-driven phosphorylation. We found that a minimal E-selectin promoter sequence necessary to confer cytokine inducibility is also sufficient to mimic the cAMP effect in transfected HUVECs. Previously we characterized two regions (NF-kappa B and NF-ELAM1) of the minimal promoter that bind transcription factors necessary for E-selectin induction, Increased cAMP did not alter the binding of the complexes formed on either the NF-kappa B or NF-ELAM1 site. In contrast, in interleukin-1-treated HUVECs transactivity due to an NF-kappa B site is reduced by elevated cAMP. Increased cAMP in HUVECs appears to induce a protein kinase activity that reduces the cytokine signal for E-selectin and VCAM-1 expression. The reduction in signal may occur through an inhibitory phosphorylation of one or more of the factors responsible for regulating E-selectin expression.
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PMID:Inhibition of E-selectin gene transcription through a cAMP-dependent protein kinase pathway. 752 80

Asthma is a disease of airway inflammation and hyper-reactivity associated with lymphocytic infiltration in the bronchial submucosa. We recently demonstrated that human airway smooth muscle (ASM) cells express the cell adhesion molecules ICAM-1 and VCAM-1, which are up-regulated by cytokines such as TNF-alpha, and which mediate binding of activated T lymphocytes. In this study, we examined whether an increase in [cAMP]i, presumably via activation of cAMP-dependent protein kinase, modulates TNF-alpha-induced ICAM-1 and VCAM-1 on ASM. We found that treatment of ASM with either forskolin, which directly activates adenylyl cyclase, or with cholera toxin, which activates the heterotrimeric GTP-binding protein, Gs, inhibited TNF-alpha-induced cell adhesion molecule expression. In addition, treatment with either isoproterenol or prostaglandin E2, which activates receptors coupled to Gs and increases [cAMP]i, also inhibited TNF-alpha-induced expression of ICAM-1 and VCAM-1 on ASM. Furthermore, adhesion of activated T cells to TNF-alpha-stimulated ASM was inhibited by treating the ASM cells with either forskolin or PGE2. These data suggest that cAMP-dependent protein kinase activation decreases cytokine-induced expression of cell adhesion molecules on ASM cells, modulates T cell binding to airway myocytes and, thus, suggests novel therapeutic approaches to airway inflammation.
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PMID:Activation of cAMP-dependent pathways in human airway smooth muscle cells inhibits TNF-alpha-induced ICAM-1 and VCAM-1 expression and T lymphocyte adhesion. 753 67

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

Monocyte adherence to the endothelium, their penetration to the subendothelial space and excessive lipid accumulation (foam cell formation) are the initial events in atherogenesis. Scavenger receptors have been reported to play an important role in foam cell formation, since modified low density lipoproteins can be taken up via scavenger receptors in a non-down-regulated fashion. In this study we demonstrate that stimulation of scavenger receptors in endothelial cells induces the expression of endothelial adhesion molecules. Polyinosinic acid (poly I), a known scavenger receptor ligand, significantly induced the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin on human umbilical vein endothelial cells when compared with polycytidylic acid (poly C), a structurally related compound to poly I, which does not bind to the scavenger receptor. The effect of scavenger receptor ligands on the endothelial cell line EA hy. 926 was also tested. Poly I up-regulated ICAM-1 expression also on EA hy. 926 cells, while it had no effect on IL-1 beta or tumour necrosis factor-alpha (TNF-alpha) production on the same cell line. Poly I-induced ICAM-1 expression on EA hy. 926 cells could be inhibited by H7, a protein kinase C inhibitor, while HA 1004, a preferential protein kinase A inhibitor, had no effect on ICAM-1 expression. The role of protein kinase C in scavenger receptor-mediated adhesion molecule upregulation was confirmed by the ability of poly I to directly activate protein kinase C, when measured with 3H-phorbol dibutyrate binding to EA hy. 926 cells, while poly C again was ineffective.
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PMID:Regulation of endothelial adhesion molecules by ligands binding to the scavenger receptor. 768 91

We examined the effect of agents which augment intracellular levels of cyclic adenosine monophosphate on the expression of adhesion molecules on human umbilical vein endothelial cells. Surface protein expression of vascular cell adhesion molecule-1, endothelial leukocyte adhesion molecule-1, or intercellular adhesion molecule-1, which is induced by tumor necrosis factor, interleukin-1, and lipopolysaccharide, was not induced by pentoxyfilline, a phosphodiesterase inhibitor, nor by dibutyryl cyclic adenosine monophosphate. Furthermore, neither of these two cyclic adenosine monophosphate elevating agents nor HA 1004, an inhibitor of the cyclic adenosine monophosphate-dependent protein kinase, had any effect on tumor necrosis factor-alpha-induced surface expression of these adhesion molecules. Likewise, cyclic adenosine monophosphate elevating agents were without effect on leukocyte adherence to endothelium stimulated either with these agents alone or in combination with tumor necrosis factor-alpha. Additionally, activators of the stimulatory or inhibitory guanine nucleotide-dependent binding proteins did not affect TNF-alpha-induced surface expression of endothelial leukocyte adhesion molecule-1 or vascular cell adhesion molecule-1.
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PMID:Cytokine-induced adhesion molecule expression on human umbilical vein endothelial cells is not regulated by cyclic adenosine monophosphate accumulation. 839 31

Ceramide generation by stimulated sphingomyelinase activity has been implicated in tumor necrosis factor alpha (TNF) signaling of apoptosis and differentiation. We examined the role of ceramide in a major action of TNF: the initiation of inflammatory events. Sphingomyelinase C at high levels induced inflammatory protein expression in endothelial cells resulting in leukocyte adhesion, but the pattern of induction of adhesion molecules (E-selectin, ICAM-1, VCAM-1) and cytokines (interleukins 6 and 8) differed from that induced by TNF. TNF induced only a small increase in ceramide: using lower doses of sphingomyelinase to mimic this we found that small amounts of ceramide did not induce protein expression, but still rapidly activated Raf-1, mitogen-activated protein/extracellular regulated kinase (ERK) kinase (MEK) and ERKs. TNF additionally caused rapid p38 and JNK-1 mitogen-activated protein kinase activation and efficient NF-kappaB translocation, which could not be achieved even by high levels of ceramide. Thus activation of the ERK cascade alone is an incomplete endothelial cell stimulus, and the TNF receptor generates at least two signals: Raf-1 activation, which could be ceramide-dependent; and ceramide-independent efficient NF-kappaB translocation and activation of p38 and JNK-1 mitogen-activated kinases.
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PMID:Endothelial cell inflammatory responses to tumor necrosis factor alpha. Ceramide-dependent and -independent mitogen-activated protein kinase cascades. 866 2

The NF-kappaB/Rel family of transcription factors regulates the inducible expression of many genes in activated human monocytes and endothelial cells. In this study, we examined the molecular mechanism by which agents that elevate intracellular cAMP inhibit the expression of the tumor necrosis factor alpha (TNFalpha), tissue factor, endothelial leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1 genes. Both forskolin and dibutyryl cAMP, which elevate intracellular cAMP by independent mechanisms, inhibited TNFalpha and tissue factor expression at the level of transcription. Induction of NF-kappaB-dependent gene expression in transiently transfected human monocytic THP-1 cells and human umbilical vein endothelial cells was inhibited by elevated cAMP and by overexpression of the catalytic subunit of protein kinase A (PKA). Elevated cAMP did not prevent nuclear translocation of p50/p65 and c-Rel/p65 heterodimers, decrease nuclear translocation of p65, or significantly modify TNFalpha-induced phosphorylation of p65. Functional studies demonstrated that transcriptional activation of a plasmid containing multimerized kappaB sites by p65 was inhibited by agents that elevate cAMP and by overexpression of the catalytic subunit of PKA. This study indicates that activation of PKA reduces the induction of a distinct set of genes in monocytes and endothelial cells by inhibiting NF-kappaB-mediated transcription.
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PMID:Elevated cyclic AMP inhibits NF-kappaB-mediated transcription in human monocytic cells and endothelial cells. 870 38

The aim of this study was to analyse the potential roles of protein kinase enzymes in tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) induced expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on human umbilical vein endothelial cells (HUVEC). The authors observed a marked increase in ICAM-1 and VCAM-1 expression on HUVEC stimulated for 24 h by TNF-alpha (10 ng/ml) or IL-1 (20 ng/ml). Pre-treatment of HUVEC for 30 min with protein tyrosine kinase (PTK) inhibitors genistein and herbimycin A (10 micrograms/ml and 0.5 microgram/ml, respectively) before stimulation with IL-1 did not affect the expression of these molecules. Similar results were observed with respect to VCAM-1 expression on HUVEC stimulated by TNF-alpha. In contrast, pre-incubation of HUVEC with PTK inhibitors prior to the addition of TNF-alpha significantly enhanced subsequent expression of ICAM-1, although spontaneous expression of ICAM-1 on unstimulated HUVEC was unaffected. Western blot analysis demonstrated a significant increase in phosphorylated tyrosine protein levels in HUVEC stimulated by TNF-alpha, and significantly lower levels of these proteins in TNF-alpha stimulated HUVEC pre-treated with PTK inhibitors. These results demonstrate that IL-1 induced ICAM-1 and VCAM-1 expression does not result from activation of PTK-dependent pathways. In the case of TNF-alpha induced responses, the selective co-stimulatory effect of this cytokine in combination with PTK inhibitors on ICAM-1 expression suggests a complicated intracellular pathway of TNF-alpha induced ICAM-1 expression, possibly involving down-modulation of increases in ICAM-1 by PTK enzymes.
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PMID:Role of tyrosine kinase enzymes in TNF-alpha and IL-1 induced expression of ICAM-1 and VCAM-1 on human umbilical vein endothelial cells. 910 26


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