Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of receptors and signaling pathways can influence the ability of dendritic cells (DC) to promote CD4(+) Th type 1 (Th1) responses. In contrast, the regulatory pathways and signaling events that govern the ability of DC to instruct Th2 cell differentiation remain poorly defined. In this report, we demonstrate that NF-kappaB1 expression within DC is required to promote optimal Th2 responses following exposure to Schistosoma mansoni eggs, a potent and natural Th2-inducing stimulus. Although injection of S. mansoni eggs induced production of IL-4, IL-5, and IL-13 in the draining lymph node of wild-type (WT) mice, NF-kappaB1(-/-) hosts failed to express Th2 cytokines and developed a polarized Ag-specific IFN-gamma response. In an in vivo adoptive transfer model in which NF-kappaB-sufficient OVA-specific DO11.10 TCR transgenic T cells were injected into OVA-immunized WT or NF-kappaB1(-/-) hosts, NF-kappaB1(-/-) APCs efficiently promoted CD4(+) T cell proliferation and IFN-gamma responses, but failed to promote Ag-specific IL-4 production. Further, bone marrow-derived DC from NF-kappaB1(-/-) mice failed to promote OVA-specific Th2 cell differentiation in in vitro coculture studies. Last, S. mansoni egg Ag-pulsed NF-kappaB1(-/-) DC failed to prime for Th2 cytokine responses following injection into syngeneic WT hosts. Impaired Th2 priming by NF-kappaB1(-/-) DC was accompanied by a reduction in MAPK phosphorylation in Ag-pulsed DC. Taken together, these studies identify a novel requirement for DC-intrinsic expression of NF-kappaB1 in regulating the MAPK pathway and governing the competence of DC to instruct Th2 cell differentiation.
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PMID:Dendritic cell-intrinsic expression of NF-kappa B1 is required to promote optimal Th2 cell differentiation. 1590 59

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

The common leucocyte antigen, CD45, is widely expressed on the surface of lymphocytes. In T and B cells, CD45 has an important role in the early events of receptor signalling. However, the role of various CD45 isoforms in B-cell receptor (BCR)- and cytokine-induced signalling and proliferation is still unclear. In the present study, we establish two follicular lymphoma cell lines expressing either CD45RA (HF28RA) or CD45R0 (HF28R0) isoforms. It was observed that the two isoforms had distinct effects on BCR- or cytokine-induced cellular proliferation. BCR stimulation significantly increased the proliferation of HF28R0 cells, in contrast to a decreased proliferation of HF28RA cells. Moreover, proliferation of HF28R0 cells significantly increased after the addition of interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-12, IL-13, IL-15, interferon-gamma and tumour necrosis factor-alpha cytokines, whereas most of these cytokines significantly inhibited the proliferation of HF28RA cells. In addition, the cell lines had their individual cytokine mRNA expression profiles after BCR stimulation. We also analysed the effect of CD45 isoforms on intracellular signalling after BCR stimulation. It was found out that the kinetics of ERK1/2 MAP kinase phosphorylation was clearly faster in HF28R0 than in HF28RA cells. The phosphorylation of other analysed MAP kinases or PTKs was very similar in the cell lines.
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PMID:CD45RA and RO isoforms have distinct effects on cytokine- and B-cell-receptor-mediated signalling in human B cells. 1596 46

Vascular endothelial cells (EC) perform critical functions that require a balance of cell survival and cell death. EC death by apoptosis and EC activation and injury by the membrane attack complex of complement are important mechanisms in atherosclerosis and organ graft rejection. Although the effects of various cytokines on EC apoptosis have been studied, little is known about their effects on complement-mediated EC injury. Therefore, we studied the abilities of various cytokines to induce protection of porcine aortic EC against apoptosis and killing by human complement, a model of pig-to-human xenotransplantation. We found that porcine EC incubated with IL-4 or IL-13, but not with IL-10 or IL-11, became protected from killing by complement and apoptosis induced by TNF-alpha plus cycloheximide. Maximal protection required 10 ng/ml IL-4 or IL-13, developed progressively from 12 to 72 h of incubation, and lasted 48-72 h after cytokine removal. Protection from complement was not associated with reduced complement activation, C9 binding, or changes in CD59 expression. Inhibition of PI3K prevented development of protection; however, inhibition of p38 MAPK or p42/44 MAPK had no effect. IL-4 and IL-13 induced rapid phosphorylation of Akt. Although protection was inhibited by an Akt inhibitor and a dominant negative Akt mutant transduced into EC, it was induced by transduction of EC with the constitutively active Akt variant, myristylated Akt. We conclude that IL-4 and IL-13 can induce protection of porcine EC against killing by apoptosis and human complement through activation of the PI3K/Akt signaling pathway.
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PMID:IL-4 and IL-13 induce protection of porcine endothelial cells from killing by human complement and from apoptosis through activation of a phosphatidylinositide 3-kinase/Akt pathway. 1603 34

The HTLV Tax protein is crucial for viral replication and for initiating malignant transformation leading to the development of adult T-cell leukemia. Tax has been shown to be oncogenic, since it transforms and immortalizes rodent fibroblasts and human T-lymphocytes. Through CREB, NF-kappaB and SRF pathways Tax transactivates cellular promoters including those of cytokines (IL-13, IL-15), cytokine receptors (IL-2Ralpha) and costimulatory surface receptors (OX40/OX40L) leading to upregulated protein expression and activated signaling cascades (e.g. Jak/STAT, PI3Kinase, JNK). Tax also stimulates cell growth by direct binding to cyclin-dependent kinase holenzymes and/or inactivating tumor suppressors (e.g. p53, DLG). Moreover, Tax silences cellular checkpoints, which guard against DNA structural damage and chromosomal missegregation, thereby favoring the manifestation of a mutator phenotype in cells.
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PMID:Molecular mechanisms of cellular transformation by HTLV-1 Tax. 1615 4

The role of p38 mitogen-activated protein kinase in primary human T cells is incompletely understood. We analyzed in detail the role of p38 in the regulation of effector functions and differentiation of human CD4 T cells by using a p38-specific inhibitor and a dominant-negative mutant of p38. p38 was found to mediate expression of IL-10 and the Th2 cytokines IL-4, IL-5, and IL-13 in both, primary naive and memory T cells. In contrast, inhibition of p38 activity did not affect expression of the Th1 cytokines IFN-gamma and TNF induced by TCR-stimulation, but decreased IL-12-mediated IFN-gamma expression. Cytokine expression from established Th2 effector cells was also regulated by p38, however, the role of p38 was less pronounced compared to primary CD4 T cells. p38 MAPK regulated cytokine gene expression at both, the transcriptional level by activating gene transcription and the post-transcriptional level by stabilizing cytokine mRNA. As a result of the effect of p38 on IL-4 expression, p38 activity modulated differentiation of naive precursor T cells by inducing a shift of the Th1/Th2 balance toward the immuno-modulatory Th2 direction. Together, the data suggest that p38 plays a key role in human Th2 cell immune responses.
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PMID:The p38 mitogen-activated protein kinase regulates effector functions of primary human CD4 T cells. 1625 5

Although the beta2-adrenergic receptor (beta2AR) is the most extensively characterized G-protein-coupled receptor (GPCR), the effects of beta-agonists on T-cell subtype function remain poorly understood. In contrast to studies suggesting lack of beta2AR expression on type 2 T cells, we demonstrate that type 2 interleukin-13+ (IL-13+) T cells (CD4+ or CD8+) in human peripheral blood lymphocytes (PBLs) can respond directly to beta-agonist, with effects including induction of protein kinase A (PKA) activity and associated inhibition of CD3-stimulated CD25 expression; CD3-stimulated IL-13, interferon-gamma (IFN-gamma), and IL-2 production; and p38 mitogen-activated protein kinase (MAPK) phosphorylation. PGE2 was more efficacious than beta-agonist in activating PKA and inhibiting cytokine production. beta-agonist and PGE2 also inhibited phorbol myristate acetate (PMA) + calcimycin-stimulated IFN-gamma and IL-2 (but not IL-13) production, suggesting that upstream CD3-initiated signaling is not the sole locus of PKA actions. Differential regulation of PMA-stimulated p38, p42/p44, and NF-kappaB explained the capacity of PGE2 and beta-agonist to inhibit IFN-gamma but not IL-13 production. The inhibition of CD3 + CD28-stimulated IL-13 production by both beta-agonist and PGE2 was reversed at low agonist concentrations, resulting in enhanced IL-13, but not IFN-gamma or IL-2, production. These findings identify direct effects of beta2AR activation on T-cell subtypes and suggest a complex role for GPCRs and PKA activity in modulating T-cell functions.
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PMID:Beta-agonists modulate T-cell functions via direct actions on type 1 and type 2 cells. 1627 2

Fyn kinase is a key contributor in coupling FcepsilonRI to mast cell degranulation. A limited macroarray analysis of FcepsilonRI-induced gene expression suggested potential defects in lipid metabolism, eicosanoid and glutathione metabolism, and cytokine production. Biochemical analysis of these responses revealed that Fyn-deficient mast cells failed to secrete the inflammatory eicosanoid products leukotrienes B4 and C4, the cytokines IL-6 and TNF, and chemokines CCL2 (MCP-1) and CCL4 (MIP-1beta). FcepsilonRI-induced generation of arachidonic acid and normal induction of cytokine mRNA were defective. Defects in JNK and p38 MAPK activation were observed, whereas ERK1/2 and cytosolic phospholipase A2 (S505) phosphorylation was normal. Pharmacological studies revealed that JNK activity was associated with generation of arachidonic acid. FcepsilonRI-mediated activation of IkappaB kinase beta and IkappaBalpha phosphorylation and degradation was defective resulting in a marked decrease of the nuclear NF-kappaB DNA binding activity that drives IL-6 and TNF production in mast cells. However, not all cytokine were affected, as IL-13 production and secretion was enhanced. These studies reveal a major positive role for Fyn kinase in multiple mast cell inflammatory responses and demonstrate a selective negative regulatory role for certain cytokines.
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PMID:Impaired FcepsilonRI-dependent gene expression and defective eicosanoid and cytokine production as a consequence of Fyn deficiency in mast cells. 1630 70

IL-13 dysregulation plays a critical role in the pathogenesis of a variety of inflammatory and remodeling diseases. In these settings, STAT6 is believed to be the canonical signaling molecule mediating the tissue effects of IL-13. Signaling cascades involving MAPKs have been linked to inflammation and remodeling. We hypothesized that MAPKs play critical roles in effector responses induced by IL-13 in the lung. We found that Tg IL-13 expression in the lung led to potent activation of ERK1/2 but not JNK1/2 or p38. ERK1/2 activation also occurred in mice with null mutations of STAT6. Systemic administration of the MAPK/ERK kinase 1 (MEK1) inhibitor PD98059 or use of Tg mice in which a dominant-negative MEK1 construct was expressed inhibited IL-13-induced inflammation and alveolar remodeling. There were associated decreases in IL-13-induced chemokines (MIP-1alpha/CCL-3, MIP-1beta/CCL-4, MIP-2/CXCL-1, RANTES/CCL-5), MMP-2, -9, -12, and -14, and cathepsin B and increased levels of alpha1-antitrypsin. IL-13-induced tissue and molecular responses were noted that were equally and differentially dependent on ERK1/2 and STAT6 signaling. Thus, ERK1/2 is activated by IL-13 in the lung in a STAT6-independent manner where it contributes to IL-13-induced inflammation and remodeling and is required for optimal IL-13 stimulation of specific chemokines and proteases as well as the inhibition of specific antiproteases. ERK1/2 regulators may be useful in the treatment of IL-13-induced diseases and disorders.
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PMID:ERK1/2 mitogen-activated protein kinase selectively mediates IL-13-induced lung inflammation and remodeling in vivo. 1637 21

IL-25 (IL-17E) induces IL-4, IL-5, and IL-13 production from an unidentified non-T/non-B cell population and subsequently induces Th2-type immune responses such as IgE production and eosinophilic airway inflammation. IL-25R is a single transmembrane protein with homology to IL-17R, but the IL-25R signaling pathways have not been fully understood. In this study, we investigated the signaling pathway under IL-25R, especially the possible involvement of TNFR-associated factor (TRAF)6 in this pathway. We found that IL-25R cross-linking induced NF-kappaB activation as well as ERK, JNK, and p38 activation. We also found that IL-25R-mediated NF-kappaB activation was inhibited by the expression of dominant negative TRAF6 but not of dominant negative TRAF2. Furthermore, IL-25R-mediated NF-kappaB activation, but not MAPK activation, was diminished in TRAF6-deficient murine embryonic fibroblast. In addition, coimmunoprecipitation assay revealed that TRAF6, but not TRAF2, associated with IL-25R even in the absence of ligand binding. Finally, we found that IL-25R-mediated gene expression of IL-6, TGF-beta, G-CSF, and thymus and activation-regulated chemokine was diminished in TRAF6-deficient murine embryonic fibroblast. Taken together, these results indicate that TRAF6 plays a critical role in IL-25R-mediated NF-kappaB activation and gene expression.
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PMID:Involvement of TNF receptor-associated factor 6 in IL-25 receptor signaling. 1639 88


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