Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intracellular protein phosphorylation is thought to be the initial step in cell activation. Bacterial lipopolysaccharide (LPS) induces a special set of the protein phosphorylation in the murine peritoneal macrophages, including p65 (molecular mass of 65 kDa) which is a substrate of serine kinase and the most dominant phosphorylated cytosolic protein. This article deals with the relation between the LPS-induced protein phosphorylation in the murine peritoneal macrophages and their productions of IL-1 beta and TNF-alpha. LPS-induced p65 phosphorylation seems to be dependent on protein kinase C (PKC) and calmodulin (CaM), because it diminishes in the presence of inhibitors to PKC or CaM. Tyrosine kinase inhibitors do not affect the p65 phosphorylation. The PKC inhibitors also affect the mRNA expressions and the productions of active molecules of IL-1 beta and TNF-alpha. Though the CaM inhibitor inhibits the mRNA expression and the active molecule production of IL-1 beta, it does not affect those of TNF-alpha. These results suggest that LPS-induced p65 phosphorylation is closely related to PKC and CaM, and that IL-1 beta production depends on PKC and CaM, while the TNF-alpha production is not dependent on CaM. These findings indicate the existence of multiple pathways and different regulatory mechanisms for transduction of LPS signal in the macrophages. Furthermore, LPS-induced phosphorylation is not observed in endotoxin tolerant macrophages after re-stimulation with LPS, suggesting that the LPS-stimulus signal is blocked at a site in the signal transduction-pathway before the point of phosphorylation of proteins in the tolerant macrophages.
 ...
PMID:Intracellular protein phosphorylation in murine peritoneal macrophages in response to bacterial lipopolysaccharide (LPS): effects of kinase-inhibitors and LPS-induced tolerance. 768 35

Asbestos and silica are well-known fibrogenic dusts. However, there is no comprehensive understanding of the molecular and cellular events that lead to fibrosis as a consequence of asbestos or silica inhalation. Previous studies have shown that asbestos stimulates superoxide anion production in alveolar macrophages through the phospholipase C/protein kinase C pathway. In contrast, silica does not appear to activate this pathway nor stimulate superoxide anion production, but silica does stimulate cytokine release by some undetermined pathway. Therefore, using human alveolar macrophages isolated from normal healthy volunteers, we evaluated the potential involvement of intracellular calcium and tyrosine kinases as potential signal transduction pathways. In the absence of serum, crystalline silica, and to a lesser extent amorphous silica, caused a rapid and dose-dependent elevation of intracellular calcium coming from the extracellular space. However, in the presence of serum, which is required for silica-stimulated cytokine release, neither form of silica caused noticeable elevation of intracellular calcium. Silica, however, did increase the extent of tyrosine phosphorylation, most notably of proteins at approximately 46 and 50 kDa, suggesting activation of a tyrosine kinase pathway. Preincubation of alveolar macrophages for 24 hr with silica-primed human alveolar macrophages for enhanced interleukin-1 beta (IL-1 beta) release stimulated by endotoxin (LPS) that was dose dependent. The enhanced LPS-stimulated release of IL-1 beta correlated with enhanced mitogen-activated protein kinase activity. Taken together, these results indicate that a tyrosine kinase pathway is activated during silica stimulation of human alveolar macrophages.
 ...
PMID:Mechanisms associated with human alveolar macrophage stimulation by particulates. 770 10

Interleukin-1 (IL-1) is a potent bone resorbing cytokine with diverse biological effects. We previously reported that IL-1 inhibits PDGF-AA-induced biological activities including PDGF-AA-induced tyrosyl phosphorylation. In the present studies, we first investigated and compared the tyrosyl phosphorylation pattern induced by EGF, IGF-1, PDGF-AA, and bFGF in human osteoblastic cells. We then examined the effect of IL-1 on the tyrosyl phosphoproteins induced by each ligand. Immunoblot analyses show that EGF, IGF-1, and PDGF-AA each elicit a different pattern of tyrosyl phosphorylated proteins in normal human osteoblastic cells. IL-1 beta inhibits PDGF-AA induced autophosphorylation by down-regulation of the PDGF-alpha receptor, as demonstrated by immunoprecipitation experiments. For other ligand-induced tyrosyl phosphoproteins, IL-1 beta reduced the intensity of EGF-induced pp55,000, and IGF-1 induced pp185,000 and pp175,000. These experiments indicate that IL-1 inhibits phosphorylation of specific proteins induced by growth factors. By using inhibitors of secondary message pathways, we determined that the inhibitory effect of IL-1 beta on PDGF-AA receptor binding and receptor tyrosyl autophosphorylation was not dependent on protein kinase A, protein kinase C, or the formation of prostaglandins. These data suggest the existence of an alternative pathway that may participate in IL-1 beta signaling.
 ...
PMID:Interleukin-1 modulates phosphorylation of proteins in human osteoblastic cells. 774 36

In this study, we compared the effects of interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) on in vitro rat gastric fundus motility. IL-1 beta and TNF produced rapid, concentration-dependent relaxation of the rat gastric fundus strips with maximal effect at 300 pg ml-1 and 10 ng ml-1, and estimated EC50S at 10 and 450 pg ml-1, respectively. The relaxant effects of IL-1 beta and TNF were not influenced by the inhibition of cyclo-oxygenase or NO-synthase activities. IL-1 beta- and TNF-induced gastric relaxations were inhibited by BW 755c, which inhibits both cyclo-oxygenase and lipoxygenase (LO), BW A4c, which selectively inhibits the 5-LO pathway, and SC 41930, a selective leukotriene B4 (LTB4) receptor antagonist, providing pharmacological evidence that LTB4 is involved in the relaxant effects of both cytokines. The IL-1 beta- and TNF-induced activation of 5-LO pathway did not appear to be triggered by phospholipase A2. An alternative pathway could involve the activation of a phospholipase C, specific for phosphatidylcholine, from which, in sequence: the formation of diacylglycerol (DAG), DAG-induced activation of protein kinase C and the formation of free arachidonic acid from DAG would ensue. This mechanism is suggested by the finding that LTB4 is able to mimic cytokine-induced strip relaxation only in the presence of phorbol 12-myristate 13-acetate, which selectively activates protein kinase C.
 ...
PMID:Interleukin-1 beta- and tumour-necrosis-factor-induced inhibition of rat gastric fundus motility in vitro. 783 Nov 92

In human umbilical endothelial cells, treatment with tumor necrosis factor (TNF)-alpha stimulated the production of cell-associated interleukin (IL)-1 alpha. Combined treatment of human umbilical endothelial cells with TNF-alpha and the protein kinase C (PKC) activator 12-O-tetradecanoylphorbol 13-acetate (TPA) suppressed the TNF-alpha-induced production of IL-1 alpha. However, concentrations of 6-keto-prostaglandin F1 alpha in the conditioned medium were increased to a greater extent by combined treatment with TNF-alpha and TPA than by single treatment with TNF-alpha or TPA. Pretreatment with TPA for 15 min was enough to suppress the TNF-alpha-induced IL-1 alpha production. Pretreatment for 15 min with other PKC activators such as aplysiatoxin or teleocidin, also inhibited the TNF-alpha-induced IL-1 alpha production. Stimulation of cell-associated IL-1 alpha production by IL-1 beta or lipopolysaccharide was also inhibited by pretreatment with the PKC activator TPA, aplysiatoxin or teleocidin. However, treatment with the protein kinase inhibitor 1-(5-isoquinoline-sulphonyl)-2- methylpiperazine dihydrochloride (H-7) did not block the inhibitory effect of TPA, aplysiatoxin or teleocidin on the cell-associated IL-1 alpha production stimulated by TNF-alpha, IL-1 beta or lipopolysaccharide, although the PKC activator-induced stimulation of 6-keto-prostaglandin F1 alpha production was counteracted by H-7 treatment. The present work indicates that the production of cell-associated IL-1 alpha stimulated by TNF-alpha, IL-1 beta or lipopolysaccharide is inhibited by treatment with TPA, aplysiatoxin or teleocidin.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Suppression of interleukin-1 alpha production by protein kinase C activators in human vascular endothelial cells. 785 98

Very little is known about the specific regulation of PGHS-2 mRNA compared with PGHS-1 mRNA. Using normal human fibroblasts, we show that at baseline there is constitutive expression of PGHS-1 mRNA and barely detectable amounts of PGHS-2 mRNA. There was a marked increase in PGHS-2 mRNA transcription following exposure to IL-1 beta. Maximal expression of PGHS-2 mRNA occurred with concentrations of IL-1 beta > or = 1 ng/ml at 3 hours after stimulation. Downregulation of protein kinase C (PKC) activity by pretreating fibroblast cultures with PMA inhibited IL-1-induced PGHS-2 mRNA expression without affecting the constitutive expression of PGHS-1 mRNA. The addition of various PKC inhibitors also blocked the IL-1 beta induction of PGHS-2 mRNA but did not alter PGHS-1 mRNA expression; inhibitors of protein kinase A (PKA) or tyrosine kinase (TK) had only a limited effect on IL-1 beta-induced PGHS-2 mRNA expression. These findings show that IL-1 beta increases PGHS-2 mRNA, at least in part, via activation of PKC. Activation of PKA or TK appears to have a more limited role in this process.
 ...
PMID:Multiple second messenger pathways regulate IL-1 beta-induced expression of PGHS-2 mRNA in normal human skin fibroblasts. 789 94

Using a sensitive flow cytometric assay, which measures the intracellular oxidation of 2'7' dichlorofluorescein (DCFH) by H2O2, we have assessed, at a single-cell level, the effects of a variety of physiological priming agonists and cytochalasin B (CB) on purified populations of neutrophils stimulated at different points along the signal response transduction pathway. Pretreatment of purified neutrophils with the physiological priming agonists monocyte interleukin-8 (IL-8), granulocyte-monocyte colony-stimulating factor (GM-CSF), platelet-activating factor (PAF), IL-1 beta, tumour necrosis factor-alpha (TNF-alpha), IL-6, and non-stimulatory doses of formyl-methionyl-leucyl-phenylalanine (FMLP), resulted in an increased percentage of cells generating an oxidative burst in response to subsequent receptor stimulation with FMLP. CB had a similar but much more pronounced effect on cellular recruitment to a receptor-mediated responsive state. Activation of protein kinase C (PKC) using the phorbol ester phorbol myristate acetate (PMA) resulted in a heterogeneous response, with all cells generating H2O2, but with two populations differing in their magnitude of response. Physiological priming agonists had no effect on the heterogeneity of the PMA response. However, pretreatment with CB dramatically altered the PMA response, producing a homogeneous population highly responsive to stimulation with PKC. In contrast, direct stimulation of G proteins with fluoride (A1F-4) was primed both by physiological priming agonists and by CB. These results demonstrate that priming of neutrophils by physiological agonists involves changes at the level of signal transduction which enable a previously non-responsive cell to respond to a secondary stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Priming of the oxidative burst in human neutrophils by physiological agonists or cytochalasin B results from the recruitment of previously non-responsive cells. 795 84

We have investigated the possibility of a protein kinase participating in the signal transduction mechanisms of the interleukin-1 (IL-1) type I receptor (IL-1RI). Our data show that a protein kinase was co-precipitated with the IL-1RI from the two murine T helper cell lines D10N and EL-4. The kinase activity was detected in an in vitro kinase assay performed with the immuno beads in the presence of exogenous substrates. IL-1 treatment of the cells resulted in a rapid activation of this protein kinase in a concentration-dependent manner. Both forms of IL-1, IL-1 alpha and IL-1 beta, induced this kinase activity, whereas the IL-1 receptor antagonist (IL-1ra) was inactive. In excess IL-1ra competitively antagonized IL-1 stimulation. In the in vitro kinase assay the exogenous substrates myelin basic protein and histone H1 were phosphorylated, whereas casein or heat-shock protein HSP27 were not accepted, reflecting a certain selectivity of this protein kinase. The IL-1RI co-precipitable protein kinase showed a serine/threonine specificity and was inhibited by staurosporine, but not by inhibitors specific for protein tyrosine kinase or protein kinase C. These results show that a serine/threonine protein kinase directly interacts with the IL-1RI at the plasma membrane level of T helper cells forming a novel type of IL-1 inducible signaling complex. This protein kinase may resemble the link coupling the plasma membrane IL-1 receptor to cytosolic downstream elements in the IL-1 signaling pathway.
 ...
PMID:Interleukin-1-induced activation of a protein kinase co-precipitating with the type I interleukin-1 receptor in T cells. 802 18

To determine the effects of the pineal hormone melatonin on human monocytes, human monocytes were activated by different concentrations of melatonin. Above the activation threshold of 5 x 10(-11) M, melatonin was able to induce the cytotoxicity of human monocytes, the secretion of IL-1, and the production of reactive oxygen intermediates. Melatonin and LPS seemed to have a synergistic effect on human monocyte activation. Indeed, below their respective monocyte activation threshold (5 x 10(-11) M and 0.625 ng/ml), melatonin (10(-12) M) in association with LPS (0.2 ng/ml) was able to induce cytotoxicity, IL-1 secretion, and reactive oxygen intermediates production. Melatonin alone at 10(-12) M or LPS alone at 0.2 ng/ml did not activate monocytes. Furthermore, melatonin was able to prime the monocytes for a subsequent activation by LPS. When monocytes were activated by LPS (0.25 ng/ml) at the time that they were plated and then activated by melatonin (10(-12) M) 8 h later, no IL-1 secretion and no cytotoxicity were detected. However, when the cells were first activated by melatonin (10(-12) M), and then 8 h later by LPS (0.25 ng/ml), IL-1 secretion and monocyte cytotoxicity were observed. Above its monocyte activation threshold, melatonin induces both cell-associated IL-1 alpha and IL-1 beta activities. Below this activation threshold, i.e., at 10(-12) M, melatonin does not induce the cell-associated IL-1 alpha and IL-1 beta activities, but does induce the mRNA for both IL-1 (alpha and beta). It seems that melatonin activates monocytes through protein kinase C. These data suggest that melatonin activates monocytes and induces their cytotoxic properties, along with the IL-1 secretion.
 ...
PMID:Activation of human monocytes by the pineal hormone melatonin. 807 74

Endotoxin, interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) dose-dependently increased the expression of tissue factor and at the same time induced thrombomodulin down-regulation on the surface of cultured bovine aortic endothelial cells. Chelerythrine, a selective protein kinase C inhibitor, strongly reduced endotoxin-, IL1 beta- and TNF alpha-induced tissue factor expression but remained without effect with regard to thrombomodulin down-regulation measured in parallel. On the contrary, staurosporine, a highly potent, non-selective PKC inhibitor, simultaneously abolished tissue factor expression and thrombomodulin down-regulation induced by endotoxin, IL1 beta and TNF alpha. These results show that protein kinase C is deeply involved in the process leading to pyrogen-induced tissue factor expression and suggest that thrombomodulin down-regulation is regulated by a different pathway.
 ...
PMID:Chelerythrine, a selective protein kinase C inhibitor, counteracts pyrogen-induced expression of tissue factor without effect on thrombomodulin down-regulation in endothelial cells. 813 8


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