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)

The c-Jun NH(2)-terminal kinase isoform (JNK) 1 is implicated in type 2 diabetes. However, a potential role for the JNK2 protein kinase in diabetes has not been established. Here, we demonstrate that JNK2 may play an important role in type 1 (insulin-dependent) diabetes that is caused by autoimmune destruction of beta cells. Studies of nonobese diabetic mice demonstrated that disruption of the Mapk9 gene (which encodes the JNK2 protein kinase) decreased destructive insulitis and reduced disease progression to diabetes. CD4(+) T cells from JNK2-deficient nonobese diabetic mice produced less IFN-gamma but significantly increased amounts of IL-4 and IL-5, indicating polarization toward the Th2 phenotype. This role of JNK2 to control the Th1/Th2 balance of the immune response represents a mechanism of protection against autoimmune diabetes. We conclude that JNK protein kinases may have important roles in diabetes, including functions of JNK1 in type 2 diabetes and JNK2 in type 1 diabetes.
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PMID:Disruption of the Jnk2 (Mapk9) gene reduces destructive insulitis and diabetes in a mouse model of type I diabetes. 1586 47

Dendritic cells (DCs) are central to T cell immunity, and many strategies have been used to manipulate DCs to modify immune responses. We investigated the effects of antioxidants ascorbate (vitamin C) and alpha-tocopherol (vitamin E) on DC phenotype and function. Vitamins C and E are both antioxidants, and concurrent use results in a nonadditive activity. We have demonstrated that DC treated with these antioxidants are resistant to phenotypic and functional changes following stimulation with proinflammatory cytokines. Following treatment, the levels of intracellular oxygen radical species were reduced, and the protein kinase RNA-regulated, eukaryotic translation initiation factor 2alpha, NF-kappaB, protein kinase C, and p38 MAPK pathways could not be activated following inflammatory agent stimulation. We went on to show that allogeneic T cells (including CD4(+)CD45RO, CD4(+)CD45RA, and CD4(+)CD25(-) subsets) were anergized following exposure to vitamin-treated DCs, and secreted higher levels of Th2 cytokines and IL-10 than cells incubated with control DCs. These anergic T cells act as regulatory T cells in a contact-dependent manner that is not dependent on IL-4, IL-5, IL-10, IL-13, and TGF-beta. These data indicate that vitamin C- and E-treated DC might be useful for the induction of tolerance to allo- or autoantigens.
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PMID:Inhibition of NF-kappa B and oxidative pathways in human dendritic cells by antioxidative vitamins generates regulatory T cells. 1594 64

Antigen-specific T-cell signalling via T-cell antigen receptor stimulation was carried out in BALB/c mice immunized with the 57 kDa major antigenic component of Shigella dysenteriae 1 outer-membrane proteins. In presence of anti-CD3, the 57 kDa antigen was found to increase the level of IL-2 significantly instead of IL-4. IL-2 production in T cells was consistent with an increase in intracellular free Ca(2+) [(Ca(2+))i] concentration. The antigen-specific modulation was observed during T-cell signalling, with enhanced release of [(Ca(2+))i]. IL-2-receptor stimulation via IL-2 did not significantly induce the release of IL-2 with consistent intracellular Ca(2+) production. Furthermore, the protein tyrosine kinase was activated during anti-CD3 stimulation, which up-regulated the phosphatidylinositol kinase of p85-mediated serine kinase protein kinase-C of p70. Phosphoinositide-specific kinases are regulated by the phosphorylation of tyrosine kinase through the activation of the T-cell antigen receptor. The above findings indicate that phosphotidylinositol-3 kinase-mediated signals are up-regulated through [(Ca(2+))i], which is essential for Th1-type responses.
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PMID:Phosphotidylinositol-3 kinase-mediated signals in mice immunized with the 57 kDa major antigenic outer-membrane protein of Shigella dysenteriae type 1. 1594 27

Individual and combined effects of chorionic gonadotropin (CG), estradiol, and progesterone on the production of IFNgamma and IL-4 by human peripheral blood lymphocytes was studied in vitro together with certain intracellular mechanisms underlying the hormonal effects. High CG dose (100 IU/ml) proved to significantly decrease IFNgamma level in the T cell culture supernatant, although this effect was not observed at the background of steroid hormones. In contrast, progesterone (100 ng/ml) increased IFNgamma production by activated T lymphocytes but proved inefficient in a physiological combination with CG and estradiol. IL-4 production was almost doubled by all studied hormones and their combinations, which considerably decreased the IFNgamma/IL-4 ratio in the culture. Inhibition analysis employing blockers of cAMP-dependent protein kinase (H-89) and L-type calcium channels (verapamil) as well as an antagonist of progesterone nuclear receptors (RU-486) demonstrated that the inhibitory (for IFNgamma) and stimulatory (for IL-4) effects of CG were mediated by cAMP, while the effects of steroid hormones on the production of these cytokines were realized through genomic and non-genomic mechanisms (the latter mechanisms were largely mediated by L-type calcium channel regulation). Overall, the studied reproductive hormones could efficiently regulate synthesis of the main Th1 (IFNgamma) and Th2 (IL-4) cytokines by T lymphocytes and seem to play the key role in changing the pregnancy-specific pattern of secreted cytokines.
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PMID:[Reproductive hormones in the control of Th1/Th2 cytokine balance]. 1600 57

B cell receptor (BCR) cross-linking induces B cell proliferation and sustains survival through the phosphorylation-dependent signals. We report that a loss of the protein phosphatase component G5PR increased the activation-induced cell death (AICD) and thus impaired B cell survival. G5PR associates with GANP, whose expression is up-regulated in mature B cells of the peripheral lymphoid organs. To study G5PR function, the G5pr gene was conditionally targeted with the CD19-Cre combination (G5pr(-/-) mice). The G5pr(-/-) mice had a decreased number of splenic B cells (60% of the controls). G5pr(-/-) B cells showed a normal proliferative response to lipopolysaccharide or anti-CD40 antibody stimulation but not to BCR cross-linking with or without IL-4 in vitro. G5pr(-/-) B cells did not show abnormalities in the BCR-mediated activation of Erks and NF-kappaB, cyclin D2 induction, or Akt activation. However, G5pr(-/-) B cells were sensitive to AICD caused by BCR cross-linking. This was associated with an increased depolarization of the mitochondrial membrane and the enhanced activation of c-Jun NH(2)-terminal protein kinase and Bim. These results suggest that G5PR is required for the BCR-mediated proliferation associated with the prevention of AICD in mature B cells.
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PMID:Protein phosphatase subunit G5PR is needed for inhibition of B cell receptor-induced apoptosis. 1612 5

Impaired host defense mechanisms after major operative procedures and trauma are recognized as important factors in the development of infectious complication. Trauma is associated with impaired cellular immunity and CD4+ T cell Th2 differentiation. We have previously implicated morphine treatment as a possible mechanism for Th2 differentiation after injury. In this investigation we first establish that morphine treatment in vivo results in Th2 differentiation and that this effect is mediated through a naltrexone-sensitive opioid receptor. We investigated the intracellular mechanism by which morphine controls CD4+ T cell differentiation and demonstrate that morphine treatment in vitro 1) increases anti CD3/CD28 Ab-induced CD4+ T cell IL-4 protein synthesis, IL-4 mRNA, and GATA-3 mRNA accumulation through a pertussis toxin-sensitive receptor; 2) results in a dose-dependent increase in anti-CD3/CD28 Ab-induced CD4+ T cell cytoplasmic cAMP concentration; and 3) increases the forskolin-stimulated cytoplasmic cAMP level through a pertussis toxin-sensitive receptor. We also demonstrate that chronic morphine treatment increases anti-CD3/CD28 Ab-induced IL-4 promoter activity and IL-4 immunoprotein expression through a p38 MAPK-dependent, but protein kinase A- and Erk1/Erk2-independent, mechanism.
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PMID:Morphine induces CD4+ T cell IL-4 expression through an adenylyl cyclase mechanism independent of the protein kinase A pathway. 1627 88

Modern therapeutic methods for manipulation of gene expression in allergic diseases have been receiving increased attention in the emerging era of functional genomics. With the growing application of gene silencing technologies, pharmacological modulation of translation represents a great advance in molecular therapy for allergy. Several strategies for sequence-specific post-transcriptional inhibition of gene expression can be distinguished: antisense oligonucleotides (AS-ONs), ribozymes (RZs), DNA enzymes (DNAzymes), and RNA interference (RNAi) triggered by small interfering RNAs (siRNAs). Potential anti-mRNA drugs in asthma and other allergic disorders may be targeted to cell surface receptors (adenosine A1 receptor, high-affinity receptor Fc-epsilon RI-alpha, cytokine receptors), adhesion molecules and ligands (ICAM-1, VLA-4), ion channels (calcium-dependent chloride channel-1), cytokines and related factors (IL-4, IL-5, IL-13, SCF, TNF-alpha, TGF-beta1), intracellular signal transduction molecules, such as tyrosine-protein kinases (Syk, Lyn, Btk), serine/ threonine-protein kinases (p38 alpha MAPkinase, Raf-1), non-kinase signaling proteins (RasGRP4), and transcription factors involved in Th2 differentiation and allergic inflammation (STAT-6, GATA-3, NF-kappaB). The challenge to scientists is to determine which of the candidate targets warrants investment of time and resources. New-generation respirable AS-ONs, external guide sequence ribozymes, and RNA interference-based therapies have the potential to satisfy unmet needs in allergy treatment, acting at a more proximal level to a key etiopathogenetic molecular process, represented by abnormal expression of genes. Moreover, antisense and siRNA technologies imply a more rational design of new drugs for allergy.
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PMID:Antisense- and RNA interference-based therapeutic strategies in allergy. 1636 94

Aggregation of the type 1 Fc-epsilon receptors (Fc-epsilon-RI) on mast cells initiates a network of biochemical processes culminating in secretion of both granule-stored and de novo-synthesized inflammatory mediators. A strict control of this response is obviously a necessity; nevertheless, this regulation is hardly characterized. Here we report that a prototype inhibitory receptor, the mast cell function-associated antigen (MAFA), selectively regulates the Fc-epsilon-RI stimulus-response coupling network and the subsequent de novo production and secretion of inflammatory mediators. Specifically, MAFA suppresses the PLC-gamma2-[Ca2+]i, Raf-1-Erk1/2, and PKC-p38 coupling pathways, while the Fyn-Gab2-mediated activation of PKB and Jnk is essentially unaffected. Hence, the activities of several transcription/nuclear factors for inflammatory mediators (NF-kappaB, NFAT) are markedly reduced, while those of others (Jun, Fos, Fra, p90rsk) are unaltered. This results in a selective inhibition of gene transcription of cytokines including IL-1beta, IL-4, IL-8, and IL-10, while that of TNF-alpha, MCP-1, IL-3, IL-5, or IL-13 remains unaffected. Taken together, these results illustrate the capacity of an immunoreceptor tyrosine-based inhibitory motif-containing receptor to cause tight and specific control of the production and secretion of inflammatory mediators by mast cells.
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PMID:Selective inhibition of the Fc epsilon RI-induced de novo synthesis of mediators by an inhibitory receptor. 3070 14

The regulation of glycogen synthase kinase-3 (GSK-3) by phosphorylation at inhibitory sites has been well documented. In many, but not all, cases, the phosphatidylinositol 3-kinase pathway, and particularly the downstream kinase protein kinase B (PKB)/akt, have been shown to be responsible for GSK-3 phosphorylation. Given that no studies have ever reported cytokine-mediated phosphorylation of GSK-3, we investigated the phosphorylation of this kinase in several hemopoietic cell types in response to either interleukin (IL)-3, IL-4 or granulocyte-macrophage colony stimulating factor (GM-CSF). Each of the cytokines was able to stimulate phosphorylation of the isoforms GSK-3alpha and GSK-3beta. However, only in the case of IL-4 stimulation was there any dependence on PKB for this phosphorylation. We were clearly able to show that PKB was capable of phosphorylating GSK-3 in these cells, but studies using inhibitors of the protein kinase C (PKC) family of kinases have shown that these enzymes are more likely to play a key role in GSK-3 phosphorylation. Cytokine-mediated generation of diacylglycerol was demonstrated, supporting the possible activation of PKC family members. Thus, cytokine-dependent GSK-3 phosphorylation in hemopoietic cells proceeds primarily through PKB independent pathways.
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PMID:Cytokine-stimulated phosphorylation of GSK-3 is primarily dependent upon PKCs, not PKB. 1646 86

Th2 lymphocytes differ from other CD4+ T lymphocytes not only by their effector tasks but also by their T cell receptor (TCR)-dependent signaling pathways. We previously showed that dihydropyridine receptors (DHPR) involved in TCR-induced calcium inflow were selectively expressed in Th2 cells. In this report, we studied whether cGMP-dependent protein kinase G (PKG) activation was implicated in the regulation of DHPR-dependent calcium response and cytokine production in Th2 lymphocytes. The contribution of cGMP in Th2 signaling was supported by the following results: 1) TCR activation elicited cGMP production, which triggered calcium increase responsible for nuclear factor of activated T cell translocation and Il4 gene expression; 2) guanylate cyclase activation by nitric oxide donors increased intracellular cGMP concentration and induced calcium inflow and IL-4 production; 3) reciprocally, guanylate cyclase inhibition reduced calcium response and Th2 cytokine production associated with TCR activation. In addition, DHPR blockade abolished cGMP-induced [Ca2+]i increase, indicating that TCR-induced DHP-sensitive calcium inflow is dependent on cGMP in Th2 cells. Th2 lymphocytes from PKG1-deficient mice displayed impaired calcium signaling and IL-4 production, as did wild-type Th2 cells treated with PKG inhibitors. Altogether, our data indicate that, in Th2 cells, cGMP is produced upon TCR engagement and activates PKG, which controls DHP-sensitive calcium inflow and Th2 cytokine production.
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PMID:The cGMP/protein kinase G pathway contributes to dihydropyridine-sensitive calcium response and cytokine production in TH2 lymphocytes. 1653 16


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