interleukin-8 and herbimycin

Human CD93, also known as complement protein 1, q subcomponent, receptor (C1qRp), is selectively expressed by cells with a myeloid lineage, endothelial cells, platelets, and microglia and was originally reported to be involved in the complement protein 1, q subcomponent (C1q)-mediated enhancement of phagocytosis. The intracellular molecular events responsible for the regulation of its expression on the cell surface, however, have not been determined. In this study, the effect of protein kinases in the regulation of CD93 expression on the cell surface of a human monocyte-like cell line (U937), a human NK-like cell line (KHYG-1), and a human umbilical vein endothelial cell line (HUV-EC-C) was investigated using four types of protein kinase inhibitors, the classical protein kinase C (cPKC) inhibitor Go6976, the novel PKC (nPKC) inhibitor Rottlerin, the protein kinase A (PKA) inhibitor H-89 and the protein tyrosine kinase (PTK) inhibitor herbimycin A at their optimum concentrations for 24 hr. CD93 expression was analyzed using flow cytometry and glutaraldehyde-fixed cellular enzyme-linked immunoassay (EIA) techniques utilizing a CD93 monoclonal antibody (mAb), mNI-11, that was originally established in our laboratory as a CD93 detection probe. The nPKC inhibitor Rottlerin strongly down-regulated CD93 expression on the U937 cells in a dose-dependent manner, whereas the other inhibitors had little or no effect. CD93 expression was down-regulated by Go6976, but not by Rottlerin, in the KHYG-1 cells and by both Rottlerin and Go6976 in the HUV-EC-C cells. The PKC stimulator, phorbol myristate acetate (PMA), strongly up-regulated CD93 expression on the cell surface of all three cell-lines and induced interleukin-8 (IL-8) production by the U937 cells and interferon-gamma (IFN-gamma) production by the KHYG-1 cells. In addition, both Go6976 and Rottlerin inhibited the up-regulation of CD93 expression induced by PMA and IL-8 or IFN-gamma production in the respective cell-lines. Whereas recombinant tumor necrosis factor-alpha (rTNF-alpha) slightly up-regulated CD93 expression on the U937 cells, recombinant interleukin-1beta (rIL-1beta), recombinant interleukin-2 (rIL-2), recombinant interferon-gamma (rIFN-gamma) and lipopolysaccharide (LPS) had no effect. Taken together, these findings indicate that the regulation of CD93 expression on these cells involves the PKC isoenzymes.

Topics: Acetophenones; Benzopyrans; Benzoquinones; Carbazoles; Down-Regulation; Endothelial Cells; Flow Cytometry; Humans; Immunoenzyme Techniques; Indoles; Interferon-gamma; Interleukin-8; Isoenzymes; Isoquinolines; Lactams, Macrocyclic; Membrane Glycoproteins; Monocytes; Protein Kinase C; Protein Kinase Inhibitors; Quinones; Receptors, Complement; Rifabutin; Sulfonamides; Tetradecanoylphorbol Acetate; U937 Cells; Up-Regulation

Emerging evidence indicates that intracellular signaling cascades mediate entry of pathogenic adenoviruses into target host cells as well as some of the undesirable inflammatory responses to adenoviral gene vectors. We found that Ad19 infection of cultured human corneal fibroblasts induced IL-8 gene transcription independently of IL-1beta, TNF-alpha, and viral gene expression, suggesting that intracellular signaling events might mediate early inflammatory events in adenovirus keratitis. Heat but not UV light inactivation of the virus abrogated the effect of infection on IL-8 mRNA and protein levels, consistent with a viral binding-mediated mechanism. The tyrosine kinase inhibitor herbimycin blocked Ad19-induced IL-8 expression. Western blot analysis revealed tyrosine phosphorylation of the functionally related kinases c-Src and extracellular signal-regulated kinase (ERK) 1/2 in corneal fibroblasts within 15 min after infection. Respective inhibitors of these kinases, PP2 and PD98059, also blocked Ad19-induced IL-8 mRNA and protein expression. Application of inhibitors to Src and ERK kinase assays suggested an upstream relationship of c-Src to ERK. Finally, DNA microarray studies performed 1 h after Ad19 or mock infection of corneal fibroblasts in the presence or absence of the Src-specific inhibitor PP2 confirmed a relationship between c-Src and IL-8 expression in Ad19-infected corneal cells. c-Src may act as a global regulator of early proinflammatory host responses to Ad19 infection of the human cornea.

Topics: Adenoviruses, Human; Benzoquinones; Cells, Cultured; Cornea; CSK Tyrosine-Protein Kinase; Enzyme Activation; Enzyme Inhibitors; Fibroblasts; Gene Expression Regulation; Humans; Interleukin-1; Interleukin-8; Lactams, Macrocyclic; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Protein-Tyrosine Kinases; Pyrimidines; Quinones; Rifabutin; src-Family Kinases; Transcription, Genetic; Tumor Necrosis Factor-alpha; Virus Replication

We previously reported that the depolymerization of actin filament by cytochalasin E enhances low affinity Fcepsilon receptor II (CD23) expression on the human monocyte-like cell line, U937 (J. Clin. Immunol. 20: 235, 2000). In this study, we found that cytochalasin E strongly induces interleukin-8 through an epithelial cell line, HeLa, in dose- and time-dependent manners as assessed by enzyme-linked immunoassay and reverse transcription-polymerase chain reaction techniques. In addition, interleukin-8 production in the HeLa cells cultured with cytochalasin E was blocked in the presence of protein kinase C inhibitors, Go6976 and H-7. On the other hand, it was found that CD54 (intercellular adhesion molecule-1; ICAM-1) expression on the HeLa cells and the secretion of soluble CD54 were significantly up-regulated after culturing with cytochalasin E, and that these up-regulations of CD54 were also suppressed by Go6976. Taken together, these findings indicate that cytochalasin E activates protein kinase C under the depolymerization of actin filament, leading to the induction of interleukin-8 production and the up-regulation of CD54 in HeLa cells.

Topics: Actin Cytoskeleton; Benzoquinones; Carbazoles; Cytochalasins; Enzyme Inhibitors; HeLa Cells; Humans; Indoles; Intercellular Adhesion Molecule-1; Interleukin-8; Lactams, Macrocyclic; Protein Kinase C; Quinones; Rifabutin; Up-Regulation

All leukocytes express the cell surface glycoprotein CD45, which has intrinsic intracellular protein tyrosine phosphatase activity. CD45 is known to play a regulatory role in activation-induced signaling in lymphocytes; however, little is known of its role in non-lymphoid leukocytes. Therefore, we examined the potential effect of CD45 on chemokine-induced signaling in human neutrophils (polymorphonuclear cells, PMN). Treating isolated PMN for 2 h with an anti-CD45RB antibody (Bra11) down-modulated expression of the chemokine receptors CXCR1 and CXCR2 to 44 +/- 10% and 47 +/- 9% of their respective controls. The tyrosine kinase inhibitors genistein and herbimycin A significantly inhibited the Bra11-induced down-modulation of CXCR1 and CXCR2. Furthermore, Bra11-treated PMN were functionally inhibited in their capacity to exhibit IL-8-induced transient intracellular Ca2+ increases. Selected targeting of CXC receptors is indicated by the fact that N-formyl-Met-Leu-Phe (fMLP) receptor expression and function were not lost following Bra11 treatment. The effect of Bra11 on IL-8-mediated function and receptor expression was paralleled by decreased tyrosine phosphorylation of a 54- to 60-kDa protein. These findings indicate that CD45 can act to modulate PMN responses to chemokines; thus agents regulating CD45 can potentially modulate leukocyte traffic and may represent a novel therapeutic approach towards the treatment of inflammatory diseases.

Topics: Antibodies, Monoclonal; Antigens, CD; Benzoquinones; Cells, Cultured; Chemokine CCL2; Chemokine CCL4; Down-Regulation; Genistein; Humans; Interleukin-8; Lactams, Macrocyclic; Leukocyte Common Antigens; Macrophage Inflammatory Proteins; Neutrophils; Phosphorylation; Protein-Tyrosine Kinases; Quinones; Receptors, Chemokine; Receptors, Interleukin; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Rifabutin; Tyrosine

Helicobacter pylori strains that contain the cag pathogenicity island (PAI) elicit increased synthesis of gastric C-X-C chemokines, promote neutrophilic infiltration into the gastric epithelium, and stimulate the synthesis of interleukin-8 (IL-8) in cultured gastric epithelial cells. To investigate the effects of cag PAI genes on the transcription of the IL-8 gene, the Kato-3 gastric epithelial cell line was stably transfected with plasmid DNA containing the IL-8 gene promoter fused to a luciferase reporter gene. The resulting reporter cell line, L5F11, was used to monitor the effects of infection in cell culture by H. pylori 26695 and isogenic derivatives with null mutations in genes in the cag PAI on transcription of the IL-8 gene. We found that null mutations in eight open reading frames, including homologs of the Agrobacterium virB9, virB10, and virB11 genes, in the left half of the cag PAI abrogated the induction of IL-8 gene transcription. Further studies with the L5F11 cell line showed that IL-8 gene transcription induced by H. pylori was blocked by the protein tyrosine kinase inhibitor herbimycin A but not by the protein kinase C inhibitor calphostin C or by the protein kinase G inhibitor KT5823. IL-8 gene transcription in L5F11 cells could also be induced by the cytokine tumor necrosis factor alpha (TNF-alpha) without exposure to H. pylori. This TNF-alpha-induced IL-8 transcription was inhibited by the protein kinase A inhibitor H7, which had no significant effect on H. pylori-induced IL-8 transcription. These studies show that multiple genes in the left half of the cag PAI are essential for the transcription of the IL-8 gene in gastric epithelial cells and that this depends on protein tyrosine kinase activation.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Benzoquinones; Cell Line; Cyclic GMP-Dependent Protein Kinases; Gastric Mucosa; Genes, Bacterial; Helicobacter pylori; Interleukin-8; Lactams, Macrocyclic; Protein Kinases; Protein-Tyrosine Kinases; Quinones; Rifabutin; Transcription, Genetic; Tumor Necrosis Factor-alpha

Using human endothelial cells, we define a mechanism that accounts for the induction of interleukin 8 (IL-8) by protein I/IIf, an adhesin from Streptococcus mutans serotype f. We report that protein I/IIf interactions with endothelial cells increased the tyrosine phosphorylation of three cellular components with relative mass of 145,000, 125,000 and 70,000 in endothelial cells. These proteins were identified as phospholipase Cgamma (PLCy), focal adhesion kinase (FAK) and paxillin after immunoprecipitation with monoclonal antibodies (mAbs) and immunoblotting with antiphosphotyrosine mAbs. These results suggested that beta1 integrins could be one of the components implicated in the modulin activity of protein I/IIf. By incubating protein I/IIf with either purified alpha5beta1 integrins or with alpha5beta1 integrins overexpressing CHO cells, we demonstrated that alpha5beta1 integrins act as cell receptors for protein I/IIf. We also showed that protein I/IIf interactions with alpha5beta1 integrins lead to IL-8 secretion. Using specific inhibitors, we demonstrated that protein I/IIf-induced IL-8 release involves mitogen-activated protein kinases (MAPKs), and that PLCgamma and PKC also seem to contribute to protein I/IIf stimulation. However, PI-3K activation is not involved in IL-8 release. Altogether, these results indicate that, after binding to alpha5beta1 integrins, protein I/IIf induces IL-8 release by activating the MAPKs signalling pathways.

Topics: Adhesins, Bacterial; Animals; Apigenin; Bacterial Proteins; Benzoquinones; Cells, Cultured; CHO Cells; Cricetinae; Cytoskeletal Proteins; Endothelium, Vascular; Enzyme Inhibitors; Flavonoids; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Genistein; Guanosine Diphosphate; Humans; Immunoblotting; Integrins; Interleukin-8; Isoenzymes; Lactams, Macrocyclic; Membrane Glycoproteins; Mitogen-Activated Protein Kinases; Paxillin; Phospholipase C gamma; Phosphoproteins; Phosphorylation; Protein Binding; Protein-Tyrosine Kinases; Quinones; Receptors, Vitronectin; Rifabutin; Streptococcus mutans; Thionucleotides; Type C Phospholipases; Tyrosine

The effect of stress on the production of cytokine-induced neutrophil chemoattractant (CINC) was examined in rat C6 glioma cells. We studied the production of CINC, an interleukin-8 (IL-8) family protein, with bacterial endotoxin, H2O2, and tumor necrosis factor-alpha (TNF-alpha). Each stress induced CINC mRNA in a concentration-dependent manner. Since stress activates the protein kinases regulating nuclear transcription factors, we examined the effects of protein kinase inhibitors and the over-expression of dominant-negative Ras on CINC mRNA expression. Neither over-expression of dominant-negative Ras nor pretreatment with PD98059 (MEK-1 inhibitor), SB203580 (p38MAPK inhibitor), or GF109203X (protein kinase C (PKC) inhibitor) altered stress-induced CINC mRNA expression. This suggests that the Ras-MAPK, p38MAPK, and PKC pathways are not involved in CINC mRNA expression in glial cells. On the other hand, pretreatment with herbimycin A, a potent tyrosine kinase inhibitor, or Ro31-8220, a non-selective serine/threonine kinase inhibitor, suppressed stress-induced CINC mRNA expression. This indicates that stress-induced CINC mRNA expression is mediated by herbimycin A-, or Ro31-8220-sensitive kinases in glial cells. Since stress activates NF-kappaB and NF-IL6, we examined that the effect of herbimycin A, which suppresses CINC mRNA expression, on NF-kappaB and NF-IL6 activation. Herbimycin A suppressed NF-kappaB but not NF-IL6. These results suggest that in rat glial cells, the factors that induce CINC mRNA expression are mediated by herbimycin A-sensitive NF-kappaB activation, but not through the PKC, Ras-MAPK or p38 MAPK pathways.

Topics: Animals; Astrocytes; Benzoquinones; Calcium-Calmodulin-Dependent Protein Kinases; CCAAT-Enhancer-Binding Proteins; Chemokines, CXC; Chemotactic Factors; DNA-Binding Proteins; Enzyme Activation; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Enzymologic; Glioma; Growth Inhibitors; Growth Substances; Indoles; Intercellular Signaling Peptides and Proteins; Interleukin-8; Lactams, Macrocyclic; Maleimides; Mitogen-Activated Protein Kinases; NF-kappa B; Nuclear Proteins; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Protein Kinase C; Quinones; ras Proteins; Rats; Rifabutin; RNA, Messenger; Signal Transduction; Transcription Factors; Tumor Cells, Cultured

The expression of the seven-transmembrane domain chemokine receptors CXCR1 and CXCR2 modulates neutrophil responsiveness to the chemoattractant IL-8 and a number of closely related CXC chemokines. In the present study, we investigated the mechanism by which bacterial LPS induces the down-modulation of IL-8 responsiveness and CXCR1 and CXCR2 expression on human neutrophils. Treating neutrophils with LPS reduced IL-8R expression to 55 +/- 5% of the control within 30 min and to 23 +/- 2% within 1 h of stimulation. Furthermore, this down-modulation could not be attributed to increased concentrations of IL-8, TNF-alpha, or IL-1beta, since ELISA studies indicated that LPS-stimulated neutrophils did not release detectable amounts of these proteins before 2 h poststimulation. The tyrosine kinase (TK) inhibitors genistein and herbimycin A attenuated the LPS-mediated down-modulation of CXCR1 and CXCR2, indicating that the activation of a TK is required for LPS to mediate its effect. The effect of LPS on receptor expression paralleled the hyperphosphorylation of the protein TK p72syk. Although IL-8 induced a comparable down-modulation of CXCR1 and CXCR2, TK inhibitors did not attenuate this effect. These studies provide the first evidence of an agonist-independent, TK-dependent pathway of chemokine receptor regulation by endotoxin.

Topics: Antigens, CD; Benzoquinones; Down-Regulation; Enzyme Inhibitors; Enzyme Precursors; Genistein; GTP-Binding Proteins; Humans; Interleukin-1; Interleukin-8; Intracellular Signaling Peptides and Proteins; Lactams, Macrocyclic; Lipopolysaccharides; Molecular Weight; Neutrophil Activation; Neutrophils; Phosphorylation; Protein-Tyrosine Kinases; Quinones; Receptors, Chemokine; Receptors, Interleukin; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Rifabutin; Signal Transduction; Syk Kinase; Time Factors; Tumor Necrosis Factor-alpha; Tyrosine

Inflamed human gingival fibroblasts (HGF) of patients with chronic periodontal diseases have less active interleukin-8 (IL-8) production compared with normal HGF of volunteers with healthy gingival tissues, after stimulation with Porphyromonas gingivalis surface components such as fimbriae, lipopolysaccharide (LPS) and its lipid A, but not LPS or lipid A from other bacterial species. A decrease in number of specific binding sites for P. gingivalis fimbrial molecules in inflamed HGF is also observed by Scatchard plot analysis. A short exposure (6 h) to P. gingivalis LPS resulted in significant potentiation of the LPS-dependent IL-8 production in normal HGF, whereas a long exposure (48 h) to the LPS significantly reduced IL-8 production. Tyrosine phosphorylation of proteins of 127 kDa and 186 kDa in inflamed HGF stimulated with P. gingivalis fimbriae or its LPS was observed by immunoblotting, and these two phosphoproteins were termed tolerance-induced protein, TIP. Protein bands of 45 kDa which bound to radioiodinated P. gingivalis fimbriae in the presence and absence of fetal bovine serum (FBS), and major 73-kDa and minor 30-kDa and 45-kDa bands which bound to radioiodinated P. gingivalis LPS in the presence of FBS in normal and inflamed HGF were observed by using photocrosslinking. These findings suggest that the hyporesponsiveness of HGF induced by a prolonged exposure to P. gingivalis may emerge because of HGF damage or result from host defense in chronic periodontal lesions.

Topics: Adult; Bacterial Proteins; Benzoquinones; Blotting, Western; Cells, Cultured; Chronic Disease; Enzyme Inhibitors; Fibroblasts; Fimbriae, Bacterial; Gingiva; Gingivitis; Humans; Interleukin-8; Lactams, Macrocyclic; Peptides; Periodontitis; Porphyromonas gingivalis; Protein-Tyrosine Kinases; Quinones; Rifabutin

Interleukin-8 (IL-8) and the structurally related cytokines neutrophil-activating peptide-2 (NAP-2) and GRO alpha are powerful chemotactic agents for human neutrophils. Although these three chemokines act by binding to overlapping but not identical receptor subsets, the data available to date have stressed the similarities in their mechanisms of action. The present studies were undertaken to further our understanding of the signal transduction mechanisms associated with these neutrophil agonists. IL-8, NAP-2, and GRO alpha stimulated similar increases in the level of cytoplasmic free calcium. They were also shown to stimulate qualitatively similar increases in the levels of protein tyrosine phosphorylation. In contrast, only IL-8 enhanced the formation of phosphatidylethanol (PEt), the product catalyzed by phospholipase D (PLD) in the presence of ethanol. The formation of PEt stimulated by IL-8 was inhibited by pertussis toxin and the tyrosine kinase inhibitors erbstatin and herbimycin A. The ability of IL-8 to stimulate the activity of PLD was additively enhanced, or primed, by cytochalasin B and by tumor necrosis factor alpha. Although all three chemokines increased the level of free cytoplasmic calcium to the same extent, IL-8 was significantly more potent than either NAP-2 or GRO alpha with respect to its ability to enhance CD11b expression and to stimulate chemotactic and oxidative responses. The differences between IL-8, NAP-2, and GRO alpha in their ability to stimulate PLD is likely to be related to their respective binding affinities for the two IL-8 receptors (IL-8R-A and IL-8R-B). These results suggest that the signalling pathways activated by IL-8R-A and IL-8R-B diverge at a step preceding the activation of PLD.

Topics: Benzoquinones; beta-Thromboglobulin; Calcium; Chemokine CXCL1; Chemokines, CXC; Chemotactic Factors; Cytochalasin B; Cytokines; Enzyme Activation; Growth Substances; Humans; Hydroquinones; Intercellular Signaling Peptides and Proteins; Interleukin-8; Lactams, Macrocyclic; Macrophage-1 Antigen; Neutrophil Activation; Neutrophils; Peptides; Pertussis Toxin; Phospholipase D; Phosphorylation; Protein Processing, Post-Translational; Protein-Tyrosine Kinases; Quinones; Receptors, Interleukin; Receptors, Interleukin-8A; Respiratory Burst; Rifabutin; Signal Transduction; Tumor Necrosis Factor-alpha; Virulence Factors, Bordetella

Human neutrophils were exposed to the chemotactic factors C5a, FMLP, IL-8, leukotriene B4, and PAF, for 30 s, and subsequently analyzed for protein tyrosine phosphorylation by immunoblotting whole cell lysates with a polyclonal antiphosphotyrosine Ab. All chemotactic factors caused the rapid de novo tyrosine phosphorylation of a broad band of approximately 120 kDa and increased the phosphotyrosine content of several other proteins, including two with molecular masses of 60 and 56 kDa that were present in the unstimulated neutrophil. Tyrosine phosphorylation was evident as early as 10 s after stimulation and was maintained for 1 to 3 min before dephosphorylation occurred. The extent of tyrosine phosphorylation was dependent on the concentration of chemotactic factor, with stimulation observed at concentrations as low as 10 to 100 nM. To investigate the pathway used by chemotactic factors to transduce this signal, neutrophils were treated with PMA. PMA also stimulated tyrosine phosphorylation in the neutrophil but with a slower response time and a different pattern of affected proteins. Additional experiments suggested that tyrosine phosphorylation is involved in the regulation of the neutrophil respiratory burst because the tyrosine kinase inhibitor, herbimycin A, inhibited C5a-induced protein tyrosine phosphorylation and also prevented C5a- and FMLP-induced superoxide anion production. Herbimycin A also inhibited PMA-induced tyrosine phosphorylation and superoxide anion production. To confirm that the ability to stimulate tyrosine phosphorylation was intrinsic to the C5a receptor, tyrosine phosphorylation was examined in both undifferentiated U937 cells (C5a receptor negative) and cAMP differentiated U937 cells (C5a receptor positive). C5a induced tyrosine phosphorylation only in differentiated U937 cells. Analysis of the C5a receptor mRNA using the PCR confirmed its presence in differentiated and its absence in undifferentiated U937 cells. Therefore, C5a stimulates tyrosine phosphorylation via a receptor-mediated mechanism and U937 cells provide a system in which G-coupled receptor-mediated tyrosine phosphorylation can be investigated.

Topics: Benzoquinones; Cell Line; Chemotactic Factors; Complement C5a; Humans; In Vitro Techniques; Interleukin-8; Lactams, Macrocyclic; Leukotriene B4; Models, Biological; Molecular Weight; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Phosphoproteins; Phosphorylation; Platelet Activating Factor; Quinones; Receptor, Anaphylatoxin C5a; Receptors, Complement; Rifabutin; RNA, Messenger; Tetradecanoylphorbol Acetate; Tyrosine

Several protein kinase inhibitors (PKIs) were investigated for their effects on IL-1 beta, TNF alpha and PMA-induced IL-8 production from human umbilical vein endothelial cells (HUVEC). IL-1 beta (ED50 0.07 ng/ml), TNF alpha (ED50 100 ng/ml) and PMA (ED50 20 ng/ml) induced IL-8 production that could be detected as early as 2 h following stimulation. Staurosporine, a potent but non-specific inhibitor of protein kinases, inhibited PMA-induced (IC50 2 nM) but not IL-1 beta or TNF alpha (IC50 > 200 nM) induced IL-8 production. Neither the cAMP-dependent PKI, KT5720, nor the tyrosine PKIs, genistein, tyrphostin (1-100 microM) or lavendustin A (0.0001-1 microM), inhibited IL-8 production elicited by IL-1 beta. However, the macrolide protein kinase inhibitor geldanamycin (IC50 = 30 nM), but not the closely related analog herbimycin A (5-500 nM), inhibited IL-8 production by 60%. Northern blot analysis of IL-8 mRNA revealed that staurosporine suppressed mRNA increase following stimulation by PMA but not by IL-1. It is proposed that a novel protein kinase susceptible to geldanamycin inhibition may be involved in IL-1-mediated signal transduction.

Topics: Alkaloids; Benzoquinones; Carbazoles; Cells, Cultured; Endothelium, Vascular; Humans; Indoles; Interleukin-1; Interleukin-8; Lactams, Macrocyclic; Protein Kinase Inhibitors; Pyrroles; Quinones; Recombinant Proteins; Rifabutin; Staurosporine; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha; Umbilical Veins