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)

Baculovirus transfection strategies have proven successful at transferring foreign DNA into hepatoma cells and primary hepatocytes. When testing the utility of these methodologies in cultured hepatocytes, we discovered that the presence of baculovirus disrupts the phenobarbital (PB) gene induction process, a potent transcriptional activation event characteristic of highly differentiated hepatocytes, and repressed expression of the albumin gene. In concert with previous reports from our laboratory demonstrating that increased cAMP levels can completely repress the induction of specific cytochrome P450 (CYP) genes, cAMP concentrations and PKA activities were measured in the primary hepatocytes subsequent to baculovirus exposure. However, neither parameter was affected by the presence of the virus. To evaluate whether immune response modulation was triggered by baculovirus exposure, RNase protection assays were performed and demonstrated that baculovirus infection activates TNF-alpha, IL-1alpha and IL-1beta expression in the primary hepatocyte cultures. Immunocytochemical experiments indicated that the production of cytokines was likely due to the presence of small numbers of Kupffer cells present in the culture populations. Exogenously added TNF-alpha was also effective in repressing PB induction, consistent with other reports indicating that inflammatory cytokines are capable of suppressing expression of biotransformation enzyme systems. Comparative studies demonstrated the specificity of these effects since exposures of hepatocytes to adenoviral vectors did not result in down-regulation of hepatic gene responsiveness. These results indicate that baculovirus vectors enhance the expression of inflammatory cytokines in primary hepatocyte cultures, raising concerns as to whether these properties will compromise the use of baculovirus vectors for study of cytochrome P450 gene regulation, as well as for liver-directed gene therapy in humans.
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PMID:Baculovirus vectors repress phenobarbital-mediated gene induction and stimulate cytokine expression in primary cultures of rat hepatocytes. 1091 98

Cross-linking of FcepsilonRI induces the activation of three protein tyrosine kinases, Lyn, Syk, and Bruton's tyrosine kinase (Btk), leading to the secretion of a panel of proinflammatory mediators from mast cells. This study showed phosphorylation at Ser-473 and enzymatic activation of Akt/protein kinase B, the crucial survival kinase, upon FcepsilonRI stimulation in mouse mast cells. Phosphorylation of Akt is regulated positively by Btk and Syk and negatively by Lyn. Akt in turn can regulate positively the transcriptional activity of interleukin (IL)-2 and tumor necrosis factor (TNF)-alpha promoters. Transcription from the nuclear factor kappaB (NF-kappaB), nuclear factor of activated T cells (NF-AT), and activator protein 1 (AP-1) sites within these promoters is under the control of Akt activity. Accordingly, the signaling pathway involving IkappaB-alpha, a cytoplasmic protein that binds NF-kappaB and inhibits its nuclear translocation, appears to be regulated by Akt in mast cells. Catalytic activity of glycogen synthase kinase (GSK)-3beta, a serine/threonine kinase that phosphorylates NF-AT and promotes its nuclear export, seems to be inhibited by Akt. Importantly, Akt regulates the production and secretion of IL-2 and TNF-alpha in FcepsilonRI-stimulated mast cells. Altogether, these results revealed a novel function of Akt in transcriptional activation of cytokine genes via NF-kappaB, NF-AT, and AP-1 that contributes to the production of cytokines.
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PMID:Akt-dependent cytokine production in mast cells. 1097 38

Unlike more well-studied large heat shock proteins (hsp) that induce both T cell antiinflammatory (IL-10, IL-4) and macrophage proinflammatory (TNF-alpha, IL-15, IL-12) cytokines, hsp27, a small hsp, has been primarily identified as a substrate of mitogen-activated protein kinase-activated protein kinase-2 involved in the p38 signaling pathway and activated during monocyte IL-10 production. Hsp27 can also act as an endogenous protein circulating in the serum of breast cancer patients and a protein whose induction correlates to protection from LPS shock. However, the cytokine-stimulating properties of hsp27 have been unexplored. In this study, exogenous hsp27 is demonstrated for the first time as a potent activator of human monocyte IL-10 production, but only a modest inducer of TNF-alpha. Although exogenous hsp27 stimulation activated all three monocyte mitogen-activated protein kinase pathways (extracellular signal-related kinase (ERK) 1/2, c-Jun N-terminal kinase, and p38), only p38 activation was sustained and required for hsp27 induction of monocyte IL-10, while both ERK 1/2 and p38 activation were required for induction of TNF-alpha when using the p38 inhibitor SB203580 or the ERK inhibitor PD98059. Hsp27's transient activation of the c-Jun N-terminal kinase pathway, which can down-regulate IL-10, may contribute to its potent IL-10 induction. Hsp27's ERK 1/2 activation was also less sustained than activation by stimuli like LPS, possibly contributing to its modest TNF-alpha induction. The failure of either PD98059 or anti-TNF-alpha Ab to substantially inhibit IL-10 induction implied that hsp27 induces IL-10 via activation of p38 signaling independently of TNF-alpha activation and may be predominantly an antiinflammatory monokine stimulus.
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PMID:Exaggerated human monocyte IL-10 concomitant to minimal TNF-alpha induction by heat-shock protein 27 (Hsp27) suggests Hsp27 is primarily an antiinflammatory stimulus. 1103 3

While monocyte/macrophage (Mphi) adherence to a matrix is necessary for differentiation and prolonged survival, the effect of adherence on the signaling mechanisms responsible for Mphi activation is unknown. Lipopolysaccharide (LPS) activates Mphi by signaling through members of the mitogen activated protein kinase (MAPK) family thereby inducing transcription of proinflammatory cytokines, such as TNF-alpha. Since adherence has been shown to affect different activities of various myeloid phagocytes, we investigated whether adherence affects intracellular signaling and modulates activation of the Mphi proinflammatory phenotype. We assessed the effect of adherence on activation of rabbit alveolar Mphi by measuring LPS-induced TNF-alpha mRNA and TNF-alpha secreted product in adherent versus nonadherent cells, in vitro. The effect of adherence on LPS-induced activation of MAPK was assessed by western analysis using a dual phosphospecific antibody against p38MAPK, p42,44ERK, and p54SAPK. LPS is known to induce activation of NF-kappaB and AP-1. Modulation of these two transcription factors by LPS under adherent versus nonadherent conditions was evaluated by gel-shift analyses. The results were that adherent cells treated with LPS, 10 ng/mL or 1 microg/ml, elicited a 26- and 132-fold increase, respectively, in TNF-alpha production. Nonadherent cells did not elicit significant TNF-alpha in response to LPS. Adherence alone induced significant ERK and AP-1 activation, but did not stimulate a significant TNF-alpha response and no further activation of ERK and AP-1 was observed with LPS stimulation. Adherence alone did not activate p38MAPK or NF-kappaB, but primed Mphi for an augmented response to LPS in activation of p38, NF-kappaB and in production of TNF-alpha. We conclude that adherence primes Mphi for activation and regulates MAPK signal transduction pathways.
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PMID:Adherence regulates macrophage signal transduction and primes tumor necrosis factor production. 1104 6

The anti-inflammatory cytokine IL-10 is up-regulated in response to TNF-alpha suggesting a control mechanism of inflammation. In addition, we recently found systemic IL-10 release in response to acute stress reactions in the absence of any systemic inflammation. In vitro and in vivo studies in experimental models suggest that catecholamines induce IL-10 release via a cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) dependent pathway. Here we studied patients for plasma IL-10 after acute myocardial infarction, a very stressful event without significant signs of systemic inflammation. In fact, the activation of the sympathetic system initiated by cardiac infarction was accompanied by a temporary systemic release of IL-10. Catecholamine induced IL-10 may be released by different cells. Recently, we demonstrated that catecholamines directly stimulate the IL-10 promoter/enhancer via a cAMP/PKA pathway in monocytic cells. A cAMP responsive element (CRE) was identified as major target. Here we show that there is no influence of catecholamines on the IL-10 promoter activity in T-cells. In contrast to monocytic cells, in T-cells cAMP-induced PKA-dependent phosphorylation of the CRE-binding protein 1 (CREB-1) seems to play a marginal role in IL-10 induction, which was reflected by a low cAMP-dependent IL-10-promoter/enhancer stimulation in reporter gene assays. Thus, catecholamines are directly involved in the regulation of IL-10 expression in monocytic but not in T-cells after acute stressful conditions.
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PMID:Catecholamines induce IL-10 release in patients suffering from acute myocardial infarction by transactivating its promoter in monocytic but not in T-cells. 1110 35

In rheumatoid synovial tissues, synovial fibroblasts are activated by proinflammatory cytokines and proliferate to develop hyperplastic pannus tissues, which irreversibly damage the affected joints. We recently reported that the cyclin-dependent kinase inhibitors p16(INK4a) and p21(Cip1) are not expressed in vivo in rheumatoid synovial fibroblasts, but are readily inducible in vitro. This observation was followed by the successful treatment of rat adjuvant arthritis by local p16(INK4a) gene transfer, showing that the inhibition of the cell cycle of the synovial cells ameliorates the arthritis. In this study, we show that another animal model of rheumatoid arthritis, murine collagen-induced arthritis, can be effectively treated by local gene transfer of p21(Cip1) as well as that of p16(INK4a). The anti-arthritic effects were observed even when the treatment was conducted after the arthritis had developed. Furthermore, the effects included suppression of the expression of proinflammatory cytokines such as IL-1ss, IL-6, and TNF-alpha. Our results demonstrate that the ectopic expression of cyclin-dependent kinase inhibitors not only prevents synovial overgrowth but also ameliorates the proinflammatory milieu in the affected joints. The induction of p21(Cip1) in rheumatoid synovial tissues by pharmacological agents may also be an effective strategy to treat rheumatoid arthritis.
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PMID:Adenoviral transfer of cyclin-dependent kinase inhibitor genes suppresses collagen-induced arthritis in mice. 1112 Aug 58

Eotaxin is a potent eosinophil chemoattractant that contributes to the eosinophilia seen in asthma and other allergic disorders. Recent studies have identified human airway smooth muscle (HASM) as a rich source of eotaxin, but the factors regulating its production are poorly understood. Here we describe for the first time that beta2-agonists can inhibit cytokine-induced eotaxin release. We found that TNF-alpha stimulated eotaxin release (assayed by ELISA) from HASM cells and that the release was partially inhibited by salbutamol and salmeterol. The effect of beta2-agonists was mimicked by forskolin and 8-bromo-cAMP and potentiated by the cAMP-dependent phosphodiesterase inhibitor rolipram, suggesting that it is cAMP dependent. We also found that the cAMP inhibition was likely at the transcription stage, although experiments with the PKA inhibitors H-89 and Rp-cAMP or the PKG inhibitor KT5823 suggested that none of these kinases was involved. Partial inhibition of eotaxin release was also seen with the corticosteroids dexamethasone and fluticasone. The combined use of beta2-agonists, rolipram, and steroids abolished TNF-alpha-induced eotaxin release. These results suggest that the combination of a beta2-agonist, PDE inhibitor, and a corticosteroid may have additive beneficial effects in the treatment of the eosinophilia associated with asthma and other allergic diseases.
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PMID:Regulation of TNF-alpha-induced eotaxin release from cultured human airway smooth muscle cells by beta2-agonists and corticosteroids. 1114 14

Mitogen-activated protein (MAP) kinase activity is essential for tumor necrosis factor (TNF) alpha receptor 1 regulation of intestinal epithelial cell proliferation. However, the mechanism of TNF-alpha mediated activation of extracellular signal-regulated kinase (ERK)/M1AP kinase has not been established clearly. Both TNF-alpha and cell-permeable ceramide have been reported to increase the kinase activity of kinase suppressor of Ras (KSR). To determine the role of KSR in TNF-alpha-induced ERK1/ERK2 activation, we studied young adult mouse colon cells expressing a dominant-negative, kinase-inactive (ki) KSR. We report that TNF-alpha, a cell-permeable ceramide, and sphingomyelinase stimulate ERK1/ERK2 activation and increase the phosphoserine content of KSR, which are inhibited by kiKSR expression in intact cells. Furthermore, TNF-alpha-induced Raf-1 threonine phosphorylation, kinase activity toward MEK1, and association with KSR are also inhibited by kiKSR expression. Our data also show by sequential in vitro kinase assays that TNF-alpha enhances KSR phosphorylation of Raf-1 on threonine, enhancing Raf-1 kinase activity toward MAP kinase kinase. We therefore conclude that KSR is an essential upstream regulator of TNF-alpha-stimulated ERK1/ERK2 activation, most likely mediated via direct phosphorylation of Raf-1.
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PMID:Kinase suppressor of ras is necessary for tumor necrosis factor alpha activation of extracellular signal-regulated kinase/mitogen-activated protein kinase in intestinal epithelial cells. 1122 91

Interferons are a family of cytokines that exerts antiviral, antitumor and immunomodulatory actions by inducing a complex set of proteins. One of the best known IFN-induced protein is the dsRNA-dependent protein kinase (PKR), that mediates both antiviral and anticellular activities. PKR inhibits translation initiation through the phosphorylation of the alpha subunit of the initiation factor eIF-2 (eIF-2 alpha) and also controls the activation of several transcription factors such as NF-kappa B, p53, or STATs. In addition, PKR mediates apoptosis induced by many different stimuli, such as treatment with LPS, TNF-alpha, viral infection, or serum starvation. The mechanism of apoptosis induction by PKR involves phosphorylation of eIF-2 alpha and activation of NF-kappa B. In this way, expression of different genes is regulated by PKR. Among the genes upregulated in response to PKR are Fas, Bax and p53. The pathway of PKR-induced apoptosis involves FADD activation of caspase 8 by a mechanism independent of Fas and TNFR. Since IFNs are used as drugs for different disorders such as viral infection and cancer, understanding the pathway of apoptosis induction triggered by PKR should be useful in the rational design of IFN therapies.
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PMID:Induction of apoptosis by the dsRNA-dependent protein kinase (PKR): mechanism of action. 1123 38

Proinflammatory cytokines affect nearly all tissues and organ systems, and the vasculature is no exception. Although a considerable amount of research has focused on the role of the two most prominent proinflammatory cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), in the pathogenesis of sepsis and septic shock, the role of these and other cytokines in the pathogenesis of atherosclerotic lesions of the coronary artery, the acute ischemic event associated with myocardial infarction, the progression of myocardiopathies or the loss of myocardial function in congestive heart failure is a relatively recent discovery. Moreover, there has also been significant investigation of the cardioprotective effects of cytokines. Most of the attention has focused on the acute coronary syndromes and the myocardial suppression that takes place as a result of acute ischemia. The potential for anticytokine-based therapies in treating heart disease is great. Parenteral TNF-alpha neutralization and IL-1 receptor blockade are presently used to treat rheumatoid arthritis. Two orally effective agents, the IL-1beta-converting enzyme inhibitor and the mitogen-activating protein kinase p38 inhibitor, are currently being investigated in clinical trials.
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PMID:Proinflammatory cytokines in heart disease. 1124 92


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