Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that activation of protein kinase C (PKC) by phorbol esters induces selectively IgA synthesis by mouse B cells. In this study, we investigated the effects of a number of protein kinase inhibitors on IgA secretion induced by a recombinant murine IL-5 in LPS-stimulated mouse B cells. The results show that PKC inhibitors, such as sphingosine (SPH), staurosporine (STP) and H-7, blocked IL-5-induced IgA synthesis; the protein kinase A inhibitor HA-1004 and the inhibitor of calcium/calmodulin dependent protein kinase W-7 had no effect on IgA secretion induced by IL-5. The proliferation of the IL-5 sensitive B13 cell line in response to IL-5 was also inhibited by addition of SPH or STP or H-7. The data suggest an involvement of the PKC pathway in IL-5-induced B cell differentiation into IgA secreting cells.
Eur Cytokine Netw
PMID:IL-5-induced IgA synthesis by LPS-stimulated mouse B cells is prevented by protein kinase C inhibitors. 158 1

DFMO and IFN have both been shown to suppress the intracellular activity of ornithine decarboxylase in rapidly proliferating tissues. In addition, both agents demonstrate antiproliferative activity against human lymphoblastoid (Daudi) cells in culture. Treatment of log-phase Daudi cells with doses of 6 U/ml of IFN or 1 mM DFMO resulted in a 50% reduction of cell number 72 h after drug addition. Combination of IFN with DFMO against DAUDI cells using the isobologram method showed that the two demonstrate true antiproliferative synergy. Analysis of 2',5'-oligoadenylate synthetase (2,5A) activity in treated cells showed that both IFN alone and IFN/DFMO combination result in equivalent 2,5A induction (1800 mmol/mg/20 h) compared to control (300 mmol/mg/20 h). While 2,5A activity decreased by 50% at 48 h in cells after treatment with IFN alone, the IFN/DFMO combination remained elevated (1700 mmol/mg/20 h). Phosphodiesterase (PdE) activity in these cells showed no substantial changes with IFN, DFMO, or IFN/DFMO treatment over 72 h compared to control values. In contrast, the activity of the 68-kDa interferon induced protein kinase (PK) in IFN/DFMO-treated cells was 1.6-fold greater at 48 and 72 h than that found for IFN alone. These studies demonstrate that the synergistic antiproliferative activity of IFN/DFMO combination may be due, in part, to modification of the activity of IFN-inducible enzymes.
Lymphokine Cytokine Res 1991 Apr
PMID:Biochemical effects of human alpha interferon in combination with alpha-difluoromethylornithine on human lymphoblastoid (DAUDI) cells in culture. 165 71

The antimalignant cell activity of tumor necrosis factor (TNF) in many cell types can be enhanced by lithium chloride (LiCl). This study shows the in vitro effect of LiCl on the TNF-induced or interleukin 1 (IL-1)-induced expression of IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, IL-2, and the IL-2 receptor-alpha (IL-2R alpha). The levels of IL-6 and GM-CSF in the medium of TNF-treated L929 fibrosarcoma cells were increased by cotreatment with LiCl. In contrast, enhancement of IL-6 production by dibutyryl cyclic AMP or cycloheximide was not affected by LiCl. The production of IL-6 and GM-CSF was not correlated with sensitivity to TNF-mediated cell killing. IL-1 by itself had no measurable effects on L929 cells. However, LiCl potentiated the IL-1-induced synthesis of IL-6, GM-CSF, IL-3, and IL-2 in PC60 murine T-cell hybridoma cells. TNF alone induced only GM-CSF production in these cells, but in the presence of LiCl, increased amounts of GM-CSF as well as small amounts of IL-2 and IL-6 could be detected. It is also shown that in these PC60 cells the expression of the IL-2R alpha was induced by TNF + LiCl treatment but not by TNF alone. IL-2R alpha expression was likewise considerably enhanced by IL-1 + LiCl treatment, as compared with treatment with IL-1 alone. The effects of LiCl on the TNF-induced and the IL-1-induced gene expression seem to be independent of the protein kinase A and C pathways. These results show that LiCl can modulate both TNF-mediated cytotoxicity and TNF-induced and IL-1-induced cytokine expression, suggesting that Li+ acts early in the TNF-signaling pathway, but at a step shared with the IL-1-signaling pathway.
Cytokine 1991 Jul
PMID:Lithium chloride potentiates tumor necrosis factor-induced and interleukin 1-induced cytokine and cytokine receptor expression. 165 81

NF-kappa B is a DNA-binding regulatory factor able to control transcription of a number of genes, including human immunodeficiency virus (HIV) genes. In T cells, NF-kappa B is activated upon cellular treatment by phorbol esters and the cytokine tumor necrosis factor alpha (TNF alpha). In the present work, we investigated the molecular events leading to NF-kappa B activation by TNF alpha in a human T cell line (Jurkat) and its subclone JCT6, which presents a deficiency in the PKA transduction pathway. We found that in both cell lines, both phorbol ester and TNF alpha were able to activate NF-kappa B. Phorbol activation was positively modulated by Ca2+ influx while TNF alpha activation was not. Furthermore, while PMA activation was inhibited by the PKC inhibitor staurosporin, the TNF alpha effect was unchanged. TNF alpha did not activate cAMP production and its signal was not modulated by cAMP activators. Moreover, cAMP activators did not activate NF-kappa B in Jurkat cells. Thus, TNF alpha-induced NF-kappa B activation was found to be mediated by none of the major signal-mediating kinases such as protein kinase C (PKC), protein kinase A, or Ca(2+)-regulated kinases. Furthermore, we found that cytoplasmic acidification facilitated NF-kappa B activation by both TNF alpha and PKC, by a mechanism that increases NF-kappa B/I kappa B dissociation without affecting the NF-kappa B translocation step.
Cytokine 1991 May
PMID:NF-kappa B activation by tumor necrosis factor alpha in the Jurkat T cell line is independent of protein kinase A, protein kinase C, and Ca(2+)-regulated kinases. 165 56

In this report we show that IL-4 inhibits DNA synthesis induced by stimulation of human B cells with mitogenic doses of either soluble anti-mu mAb DA44 or phorbol ester. In contrast, earlier steps of anti-mu-induced B cell stimulation, such as RNA synthesis, CD23 expression and IL-6 production, were not inhibited but rather increased in the presence of IL-4. From these results, IL-4 appears therefore to exert two opposite effects on DA44 anti-mu mAb-induced human B cell activation: early steps are stimulated, and later steps inhibited. The results of kinetic analysis were consistent with this model. The inhibitory activity of IL-4 required an active cAMP-dependent pathway since IL-4-mediated inhibition of anti-mu-induced B cell proliferation was abolished in the presence of two specific inhibitors of the cAMP pathway (H8 and 2',5'-dideoxyadenosine which are specific for cAMP-dependent protein kinase and adenylate cyclase respectively). Furthermore, IL-4 induced a delayed and prolonged increase in intracellular cAMP concentrations (observed between 4 and 48 hours of culture), and this strongly suggests that the late inhibitory effects of IL-4 is cAMP-dependent. Moreover, this delayed IL-4-mediated cAMP production is probably sufficient to prevent anti-mu induced DNA synthesis since addition of the cAMP agonist forskolin on day 1 or 2 of culture also suppresses the anti-mu-mediated B cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)
Eur Cytokine Netw
PMID:IL-4 counteracts anti-mu-induced human B cell proliferation: involvement of a cAMP-dependent inhibitory pathway. 172 49

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) enhanced the phosphorylation of identical cytosolic 65 kDa protein (P65 or l-plastin) and 74 kDa protein (P74) at serine residues in human peripheral blood mononuclear cells (PBMC). The isoelectric points of P65 and P74 were 5.6 and 4.7 to 5.0, respectively. The phosphorylation of these proteins increased with a few minutes and reached maximal levels of approximately 3 times the unstimulated levels by 10 minutes. The phosphorylation of P65 and P74 was extensively enhanced by a potent protein kinase C (PKC) activator, PMA. However, there was no translocation of PKC from cytosol to membrane in PBMC that was stimulated with either TNF or IL-1, which suggests that PKC does not participate in TNF or IL-1 signal transduction. cAMP dependent protein (PKA) activators, forskolin and PGE2, failed to increase the phosphorylation, which is in agreement with the data showing that neither TNF nor IL-1 increased cAMP levels in PBMC. These results suggest that induction of phosphorylation of P65 and P74 by TNF and IL-1 is not mediated by PKC and PKA but may be mediated by another protein kinase and result in overlapping of biological activities between TNF and IL-1.
Cytokine 1990 Jan
PMID:Enhanced phosphorylation of 65 and 74 kDa proteins by tumor necrosis factor and interleukin-1 in human peripheral blood mononuclear cells. 196 46

Cytokines are soluble informational polypeptides which modulate cellular functions by combining with specific membrane receptors in the originating cell (autocrine), a regional cell (paracrine) or a distant cell (endocrine). Cytokine-receptor complexes usually initiate signal transduction via protein kinase phosphorylation or G-protein dependent phospholinositol changes which further alter cell function. In the exuberant fibrosis of scleroderma, fibroblasts are activated to secrete several extracellular matrix molecules (collagens, fibronectin, proteoglycans) and they also fail to respond to the usual cell growth signals in vitro. We have studied the hypothesis that cytokines released through the T-cell dependent activation/injury of the vascular and microvascular endothelium initiate activation of the scleroderma fibroblast. Recalling that cell activation can occur either by removal of suppression or direct activation and that the locus of action can be transcriptional, translational or post-translational or a combination of these, our studies have focused on the cytokine transforming growth factor beta (TGF-beta) family of molecules, on the matrix gene expression abnormality of the scleroderma fibroblast and on the activation by TGF-beta of the platelet derived growth factor (PDGF) family of cytokines to explain the persistent cell growth abnormality. Our findings include: 1. Scleroderma fibroblasts are equally responsive to TGF-beta as are healthy fibroblasts with regard to collagen synthesis and they bind TGF-beta in all parameters similar to the binding to healthy fibroblasts. 2. TGF-beta is a stronger mitogenic signal to scleroderma fibroblasts than to control fibroblasts in the presence of serum.(ABSTRACT TRUNCATED AT 250 WORDS)
Eur Cytokine Netw
PMID:Cytokines and human fibrosis. 196 52

The effect of the human rIL-1 alpha and rTNF-alpha on the binding of 125I-labeled epidermal growth factor ([125I]EGF) to its receptor (EGF-R) has been studied in human gingival fibroblasts (HuGi). Incubation of these cells with recombinant cytokines at 37 degrees C caused a rapid, dose-dependent decrease in their ability to subsequently bind subsaturating levels of [125I]EGF at 4 degrees C. Inhibition was evident at 5 min after addition of cytokines, reached a maximal level (60-70% reduction) after 15 to 30 min, and declined thereafter. Normal EGF binding was attained by 2 h. Half-maximal inhibition of EGF binding occurred at 10 pM IL-1 and 50 pM TNF. The two cytokines were not additive in their effect. Competition experiments at 4 degrees C showed that the cytokines did not interact directly with EGF-R; Scatchard analysis of binding of [125I]EGF to HuGi after treatment with IL-1 and TNF revealed an increase in EGF-R Kd from 0.75 nM to 2.9 nM with no change in receptor number. The effect of IL-1 and TNF on EGF-R was compared with that of the tumor-promotor PMA which is known to "transmodulate" EGF-R affinity by activating protein kinase C which then phosphorylates EGF-R. PMA caused a greater inhibition of EGF binding to HuGi (80 to 85% inhibition; ED50 = 500 pM), and recovery of binding was much slower. Importantly, in HuGi made deficient in protein kinase C by prolonged incubation with PMA, addition of fresh PMA no longer affected EGF binding, while the response to IL-1 and TNF was intact. Cytokine- but not PMA-mediated EGF-R transmodulation was partially reversed by treatment of the cells with millimolar concentrations of the kinase inhibitor amiloride. HuGi were incubated with H3 32PO4, stimulated with PMA or cytokines, and EGF-R were immunoprecipitated; IL-1 and TNF, like PMA, caused a 2- to 5-fold increase in receptor phosphorylation. We conclude that occupation of IL-1 and TNF-R activates a protein kinase, distinct from kinase C, for which EGF-R is a substrate.
 ...
PMID:IL-1 and TNF transmodulate epidermal growth factor receptors by a protein kinase C-independent mechanism. 278 20

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.
 ...
PMID:Cytokine-activated endothelial cells internalize E-selectin into a lysosomal compartment of vesiculotubular shape. A tubulin-driven process. 751 27

Cytokines are known to be important regulators of normal hemopoiesis, acting in concert with components of the bone marrow microenvironment. Interactions with this microenvironment are known to regulate the proliferation, differentiation, and homing of hemopoietic progenitor (CD34+) cells. Adhesive interactions with the extracellular matrix retain CD34+ cells in close proximity to cytokines, but may also provide important costimulatory signals. Thus, the functional states of adhesion receptors are critical properties of CD34+ cells, but the physiological mechanisms responsible for regulating functional properties of cell adhesion receptors on primitive hemopoietic cells are still unknown. We confirm that the integrins very late antigen (VLA)-4 and VLA-5 are expressed on the CD34+ cell lines MO7e, TF1, and on normal bone marrow CD34+ progenitor cells, but in a low affinity state, conferring on them a weak adhesive phenotype on fibronectin (Fn). Herein, we show that the cytokines interleukin (IL)-3, granulocyte-macrophage CSF (GM-CSF), and KIT ligand (KL) are physiological activators of VLA-4 and VLA-5 expressed by MO7e, TF1, and normal bone marrow CD34+ progenitor cells. Cytokine-stimulated adhesion on Fn is dose dependent and transient, reaching a maximum between 15 and 30 min and returning to basal levels after 2 h. This cytokine-dependent activation is specific for VLA-4 and VLA-5, since activation of other beta 1 integrins was not observed. The addition of second messenger antagonists staurosporine and W7 abolished all cytokine-stimulated adhesion to Fn. In contrast, genistein inhibited KL-stimulated adhesion, but failed to inhibit GM-CSF- and IL-3-stimulated adhesion. Our data suggest that cytokines GM-CSF and IL-3 specifically stimulate beta 1 integrin function via an "inside-out" mechanism involving protein kinase activity, while KL stimulates integrin activity through a similar, but initially distinct, pathway via the KIT tyrosine-kinase. Thus, in addition to promoting the survival, proliferation, and development of hemopoietic progenitors, cytokines also regulate adhesive interactions between progenitor cells and the bone marrow microenvironment by modifying the functional states of specific integrins. These data are of importance in understanding the fundamental processes of beta 1 integrin activation and cellular response to mitogenic cytokines as well as on the clinical setting where cytokines induce therapeutic mobilization of hematopoietic progenitors.
 ...
PMID:Cytokines increase human hemopoietic cell adhesiveness by activation of very late antigen (VLA)-4 and VLA-5 integrins. 753 95


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