Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stimulation of hemopoietic cells with IL-3, IL-4, IL-5, granulocyte-macrophage-CSF and Steel factor-(SLF) induced tyrosine phosphorylation of a number of protein substrates. Two of these proteins, designated p42 and p44, were tyrosine phosphorylated rapidly in response to treatment with IL-3, IL-5, granulocyte-macrophage-CSF and SLF, but not IL-4. We demonstrate that these common substrates are members of the mitogen-activated protein kinase (MAP kinase) family of protein serine/threonine kinases. Ion-exchange chromatography yielded a peak of MAP kinase activity eluting at 0.3 to 0.32 M NaCl. Immunoblotting of column fractions with antiphosphotyrosine antibodies showed coelution of the peak of MAP kinase enzyme activity with the p42 and p44 tyrosine phosphorylated species, and with two proteins of 42 and 44 kDa which were immunoreactive with anti-MAP kinase antibodies. Moreover, a characteristic shift in mobility of the p42 and p44 species was observed after factor treatment. Time-course analyses and subsequent ion-exchange chromatography demonstrated SLF activation of MAP kinase activity was maximal after 2 min of factor treatment and decreased to basal levels after 30 min stimulation. By contrast, activation of MAP kinase after IL-5 treatment was not as rapid. Maximal activity was observed 15 min after stimulation and remained elevated for up to 60 min after IL-5 addition. Investigation of the role of protein kinase C in the mechanism of activation by these growth factors demonstrated that specific inhibition of protein kinase C led to a reduction, but not ablation, of the SLF and IL-3 induced stimulation of MAP kinase activity. The use of synthetic peptide substrates confirmed SLF and IL-5 activate isoforms of MAP kinases. These results demonstrate that members of the MAP kinase family are involved in common signal transduction events elicited by IL-3, IL-5, granulocyte-macrophage-CSF and Steel factor, but not those involving IL-4.
 ...
PMID:Multiple hemopoietic growth factors stimulate activation of mitogen-activated protein kinase family members. 138 May 36

Here we report that IL-4 specifically enhances cell surface expression of CXCR4 on resting peripheral and cord blood T cells. Whereas polarized Th2 clones express variable levels of CXCR4, expression of this receptor is undetectable on polarized Th1 clones but can be induced on the latter cells as well, following short-term culture in the presence of IL-4. The IL-4-induced CXCR4 is functional since interaction with its ligand, stromal-derived factor (SDF)-1, activates the p42 MAP-kinase ERK-2. In addition, although CXCR4 expression is down-regulated following stimulation of T cells and T cell clones via CD28 or CD3 and CD2 cell surface molecules, respectively, it is re-induced by IL-4. These data indicate an important role for IL-4 in rendering CD4+ T cells susceptible to infection with HIV via CXCR4, as well as in promoting SDF-1-induced migration of these cells.
 ...
PMID:IL-4 induces functional cell-surface expression of CXCR4 on human T cells. 957 13

Eosinophils, along with mast cells are key cells involved in the innate immune response against parasitic infection whereas the adaptive immune response is largely dependent on lymphocytes. In chronic parasitic disease and in chronic allergic disease, IL-5 is predominantly a T cell derived cytokine which is particularly important for the terminal differentiation, activation and survival of committed eosinophil precursors. The human IL-5 gene is located on chromosome 5 in a gene cluster that contains the evolutionary related IL-4 family of cytokine genes. The human IL-5 receptor complex is a heterodimer consisting of a unique alpha subunit (predominantly expressed on eosinophils) and a beta subunit which is shared between the receptors for IL-3 & GM-CSF (more widely expressed). The alpha subunit is required for ligand-specific binding whereas association with the beta subunit results in increased binding affinity. The alternative splicing of the alpha IL-5R gene which contains 14 exons can yield several alpha-IL-5R isoforms including a membrane-anchored isoform (alpha IL-5Rm) and a soluble isoform (alpha IL-5Rs). Cytokines such as IL-5 produce specific and non-specific cellular responses through specific cell membrane receptor mediated activation of intracellular signal transduction pathways which, to a large part, regulate gene expression. The major intracellular signal transduction mechanism is activation of non-receptor associated tyrosine kinases including JAK and MAP kinases which can then transduce signals via a novel family of transcriptional factors named signal transducers and activators of transcription (STATS). JAK2, STAT1, and STAT5 appear to be particularly important in IL-5 mediated eosinophil responses. Asthma is characterized by episodic airways obstruction, increased bronchial responsiveness, and airway inflammation. Several studies have shown an association between the number of activated T cells and eosinophils in the airways and abnormalities in FEV1, airway reactivity and clinical severity in asthma. It has now been well documented that IL-5 is highly expressed in the bronchial mucosa of atopic and intrinsic asthmatics and that the increased IL-5 mRNA present in airway tissues is predominantly T cell derived. Immunocytochemical staining of bronchial biopsy sections has confirmed that IL-5 mRNA transcripts are translated into protein in asthmatic subjects. Furthermore, the number of activated CD4 + T cells and IL-5 mRNA positive cells are increased in asthmatic airways following antigen challenge and studies that have examined IL-5 expression in asthmatic subjects before and after steroids have shown significantly decreased expression following oral corticosteroid treatment in steroid-sensitive asthma but not in steroid resistant and chronic severe steroid dependent asthma. The link between T cell derived IL-5 and eosinophil activation in asthmatic airways is further strengthened by the demonstration that there is an increased number of alpha IL-5R mRNA positive cells in the bronchial biopsies of atopic and non-atopic asthmatic subjects and that the eosinophil is the predominant site of this increased alpha IL-5R mRNA expression. We have also shown that the subset of activated eosinophils that expressed mRNA for membrane bound alpha IL-5r inversely correlated with FEV1, whereas the subset of activated eosinophils that expressed mRNA for soluble alpha IL-5r directly correlated with FEV1. Hence, not only does this data suggest that the presence of eosinophils expressing alpha IL-5R mRNA contribute towards the pathogenesis of bronchial asthma, but also that the eosinophil phenotype with respect to alpha IL-5R isoform expression is of central importance. Finally, there are several animal, and more recently in vitro lung explant, models of allergen induced eosinophilia, late airway responses (LARS), and bronchial hyperresponsiveness (BHR)--all of which support a link between IL-5 and airway eosinophilia and bronc
 ...
PMID:IL-5 and IL-5 receptor in asthma. 969 19

Recently we showed that human epidermal keratinocytes express the extracellular matrix protein tenascin-C (TN-C) during wound healing, but not in normal adult skin. To gain further insight into the regulation of epidermal TN-C expression, we tested the effect of various stimuli on TN-C expression by cultured keratinocytes. Our results indicate that IL-4 is a very strong inducer of TN-C protein and mRNA expression in normal keratinocytes. Furthermore, TNFalpha and IFNgamma moderately increased TN-C expression. No other cytokines and growth factors that we tested, including various factors that stimulate TN-C expression in mesenchymal cells, significantly affected TN-C secretion by cultured keratinocytes. The regulation of TN-C expression in keratinocytes is distinct from that of fibronectin, since IL-4 and IFNgamma did not affect fibronectin expression in our experiments, and TNFalpha only slightly increased fibronectin levels. To investigate the role of cellular stress response pathways that can be activated by TNFalpha in the regulation of TN-C expression, we tested the effect of different inhibitors and an activator of these intracellular signalling cascades. The results show that the p38 MAP-kinase pathway is not involved in TNFalpha-induced TN-C expression in cultured keratinocytes. Activation of the JNK/SAPK-1 pathway by the addition of sphingomyelinase resulted in a dose-dependent increase of TN-C expression. TN-C expression by squamous carcinoma cell lines was differentially affected by the cytokines that stimulated TN-C expression in normal keratinocytes: TNFalpha again increased TN-C secretion, but IL-4 and IFNgamma had little effect. We conclude that there are distinct regulation mechanisms for TN-C expression in normal keratinocytes, tumor-derived keratinocytes and mesenchymal cells. The observation that TN-C is abundant in inflamed skin is a strong indication that inflammatory cytokines such as IL-4, TNFalpha and IFNgamma could also be involved in the regulation of epidermal TN-C expression in vivo.
 ...
PMID:Tenascin-C expression in human epidermal keratinocytes is regulated by inflammatory cytokines and a stress response pathway. 974 46

Ligation of CD40 on monocytes through its interaction with CD40 ligand (CD154) present on activated T helper cells, results in activation of monocyte inflammatory cytokine synthesis and rescue of monocytes from apoptosis induced through serum deprivation. Both of these consequences of CD40 stimulation have been shown to be dependent on the induction of protein tyrosine kinase activity. CD40-mediated activation of protein tyrosine kinase activity and subsequent inflammatory cytokine production are abrogated by treatment of monocytes with the T helper type 2 cytokines interleukin 4 (IL-4) and interleukin 10 (IL-10). In the current study we demonstrate that stimulation of monocytes through CD40 resulted in the phosphorylation and activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein kinases, whereas phosphorylation of mitogen-activated protein kinases family members p38 and c-Jun N-terminal kinase was not observed in response to this stimuli over the time course examined. PD98059, an inhibitor of the upstream activator of ERK1/2, the MAP/ERK kinase MEK1/2, suppressed IL-1beta and tumor necrosis factor-alpha production in a dose-dependent fashion. Pretreatment of monocytes with IL-4 and IL-10 inhibited CD40-mediated activation of ERK1/2 kinase activity when used individually, and are enhanced in effectiveness when used in combination. Together, the data demonstrate that CD40-mediated induction of IL-1beta and tumor necrosis factor-alpha synthesis is dependent on a MEK/ERK pathway which is obstructed by signals generated through the action of IL-4 and IL-10.
 ...
PMID:CD40 signaling of monocyte inflammatory cytokine synthesis through an ERK1/2-dependent pathway. A target of interleukin (il)-4 and il-10 anti-inflammatory action. 1002 6

ICAM-1 is an Ig-like cell adhesion molecule expressed by several cell types, including the endothelium. Cross-linking of ICAM-1 on the surface of different cell types has previously been shown to cause an increase in cellular activation within the cytoplasm. In this study, we have compared signaling events following ligation of ICAM-1 by cross-linking with mAbs with events after activation of HUVEC by TNF. ICAM-1 cross-linking caused activation of Erk-1 and the AP-1 transcription factor complex, without any increase in NF-kappaB activity, in contrast to TNF stimulation. Transcription of VCAM-1 mRNA was observed by reverse-transcriptase PCR after ICAM-1 cross-linking, with no associated transcription of E-selectin. This was reflected by the presence of VCAM-1 protein after immunoprecipitation, without E-selectin expression, in ICAM-1 cross-linked cells. In contrast, mRNA and protein for both VCAM-1 and E-selectin were observed in TNF-treated HUVEC, as expected. Addition of the MEK (MAP/Erk kinase) inhibitor PD98059 reduced expression of VCAM-1 after ICAM-1 cross-linking, suggesting that the Erk pathway is involved in ICAM-1-mediated VCAM-1 expression. In conclusion, ICAM-1-induced expression of VCAM-1 represents a pathway for adhesion molecule up-regulation that is distinct from the TNF-induced pathway. It may be similar to the IL-4 pathway or it may represent a novel pathway.
 ...
PMID:Ligation of ICAM-1 on endothelial cells leads to expression of VCAM-1 via a nuclear factor-kappaB-independent mechanism. 1007 50

Despite the anti-TNF alpha based progress in the treatment of RA, it is necessary to further optimize study designs and reports (Etanercept/MTX combination with results of radiological progression; publication of D2E7 trials; combination of D2E7 with MTX). Moreover, innovative immunobiologicals (PEG-TNFRI, PEG-TNF alpha antibody fragments, soluble TNFRI, CTLA4-Ig, CD40 ligand antibody, antibodies against IFN-gamma, IL-6, IL-12, IL-15, IL-18, complements), inhibitors of TNF alpha translation (peptides, anti-sense constructs) or TNF alpha synthesis (targeting NF kappa B, p38 MAP-kinase, phosphodiesterase IV, TNF alpha converting enzyme) are forthcoming. Principally different are inhibitors of complement convertases or collagenase as well as vaccination studies or trials trying to induce T cell anergy. Furthermore, for patients with MTX side effects, alternative DMARDs need to be tested along with TNF alpha blockers. Combination studies of TNF alpha constructs with other immunobiologicals (anti-CD4, IL-4, IL-10, IL-1RA) should be evaluated. To date, TNF alpha blockers have been evaluated in very early RA. Finally, a step-down trial will test whether--after induction of remission with a TNF alpha blocker plus MTX--replacement of the TNF alpha blocker with MTX alone or in combination with leflunomide will be able to keep disease activity suppressed for a longer duration.
 ...
PMID:[New therapy developments in rheumatoid arthritis]. 1175 32

CD4+ T lymphocytes are divided in Th1 cells producing IFN gamma and Th2 cells that synthetize IL-4. This paper describes signaling pathways activated following T cell receptor (TCR) engagement and emphasizes differences that can account for differential cytokine production. This paper focuses on a new signaling pathway involved in IL-4 synthesis. This pathway couples the TCR to PKC that controls a calcium entry through dihydropyridine sensitive calcium channels. The calcium response is sufficient to initiate IL-4 gene transcription. Differing from that of IL-4, IFN gamma gene expression always requires MAP-kinase activation in addition to a calcium signal.
 ...
PMID:[Calcium-dependent pathways involved in the production of cytokines in lymphocytes]. 1183 69

Hepatocyte growth factor (HGF) regulates various physiological and developmental processes in concert with other growth factors, cytokines and hormones. We examined interactions between cell signaling events elicited by HGF and the cytokine interleukin (IL)-4, in the IL-3-dependent murine myeloid cell line 32D transfected with the human HGF receptor, c-Met. HGF was a potent mitogen in these cells, and prevented apoptosis in response to IL-3 withdrawal. IL-4 showed modest anti-apoptotic activity, but no significant mitogenic activity. IL-4 synergistically enhanced HGF-stimulated DNA synthesis, whereas only additive prevention of apoptosis was observed. IL-4 did not enhance HGF-dependent tyrosine phosphorylation of c-Met or Shc. In contrast, HGF-stimulated activation of MAP kinases was enhanced by IL-4, suggesting that the IL-4 and HGF signaling pathways converge upstream of these events. Although phosphatidylinositol 3-kinase (PI3K) inhibitors diminished HGF-induced mitogenesis, anti-apoptosis, and MAP kinase activation, IL-4 enhanced HGF signaling persisted even in the presence of these inhibitors. IL-4 enhancement of HGF signaling was partially blocked in 32D/c-Met cells treated with inhibitors of MEK1 or c-Src kinases, completely blocked by expression of a catalytically inactive mutant of Janus kinase 3 (Jak3), and increased in 32D/c-Met cells overexpressing STAT6. Our results suggest that the IL-4 and HGF pathways converge at multiple levels, and that IL-4-dependent Jak3 and STAT6 activities modulate signaling events independent of PI3K to enhance HGF-dependent mitogenesis in myeloid cells, and possibly other common cellular targets.
 ...
PMID:Mitogenic synergy through multilevel convergence of hepatocyte growth factor and interleukin-4 signaling pathways. 1194 3

JAK/STAT pathways are described as the major mechanisms by which cytokine receptors transduce intracellular signals. The signalling mechanisms in antigen-presenting cells (APC) in the sensitization phase of contact hypersensitivity are poorly understood. The aim of this study was to clarify whether well-established JAK/STAT signalling pathways might be activated directly by contact sensitizers as described previously for tyrosine kinases and some MAP kinases. As a model of epidermal APC, human monocytes and human monocyte-derived dendritic cells were stimulated with the structurally unrelated contact sensitizers MCI/MI, thimerosal, TNCB and formaldehyde. The phosphorylation states of the transcription factors STAT1, STAT3, STAT4, STAT5 and STAT6 were determined by Western blot analysis using phosphospecific antibodies. In contrast to the positive controls performed with the cytokines IFN-gamma, IL-10, IFN-alpha, GM-CSF and IL-4, no significant increase in the phosphorylation of STAT molecules was recognized in hapten-treated cells. These results suggest that contact allergens do not directly activate common JAK/STAT pathways. Therefore the activation of APC in the early sensitization phase of contact hypersensitivity by haptens does not involve signals normally delivered by JAK-associated cytokine receptors.
 ...
PMID:JAK/STAT pathways are not involved in the direct activation of antigen-presenting cells by contact sensitizers. 1211 45


1 2 3 4 5 Next >>