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)

Interleukin-13 (IL-13), a Th2 cytokine, plays a pivotal role in pathogenesis of bronchial asthma via IL-13 receptor alpha1 (IL-13Ralpha1) and IL-4 receptor alpha (IL-4Ralpha). Recent studies show that a decoy receptor for IL-13, namely IL-13Ralpha2, mitigates IL-13 signaling and function. This study provides evidence for regulation of IL-13Ralpha2 production and release and IL-13-dependent signaling by lysophosphatidic acid (LPA) in primary cultures of human bronchial epithelial cells (HBEpCs). LPA treatment of HBEpCs in at imedependent fashion increased IL-13Ralpha2 gene expression without altering the mRNA levels of IL-13Ralpha1 and IL-4Ralpha. Pretreatment with pertussis toxin (100 ng/ml, 4 h) or transfection of c-Jun small interference RNA or an inhibitor of JNK attenuated LPA-induced IL-13Ralpha2 gene expression and secretion of soluble IL-13Ralpha2. Overexpression of catalytically inactive mutants of phospholipase D (PLD) 1 or 2 attenuated LPA-induced IL-13Ralpha2 gene expression and protein secretion as well as phosphorylation of JNK. Pretreatment of HBEpCs with 1 microM LPA for 6 h attenuated IL-13-but not IL-4-induced phosphorylation of STAT6. Transfection of HBEpCs with IL-13Ralpha2 small interference RNA blocked the effect of LPA on IL-13-induced phosphorylation of STAT6. Furthermore, pretreatment with LPA (1 microM, 6 h) attenuated IL-13-induced eotaxin-1 and SOCS-1 gene expression. These results demonstrate that LPA induces IL-13Ralpha2 expression and release via PLD and JNK/AP-1 signal transduction and that pretreatment with LPA down-regulates IL-13 signaling in HBEpCs. Our data suggest a novel mechanism of regulation of IL-13Ralpha2 and IL-13 signaling that may be of physiological relevance to airway inflammation and remodeling.
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PMID:Lysophosphatidic acid induces interleukin-13 (IL-13) receptor alpha2 expression and inhibits IL-13 signaling in primary human bronchial epithelial cells. 1728 16

Eosinophils develop from stem cells in the bone marrow under the influence of hematopoietic cytokines, particularly IL-5. Previously, we have demonstrated that blockage of Notch signaling by a gamma-secretase inhibitor (GSI) promotes the differentiation of umbilical cord blood (UCB)-derived eosinophils. These highly major basic protein (MBP)-positive eosinophils cultured in the presence of the inhibitor lack the migratory response to eotaxin, although their CCR3 levels are similar to those of eosinophils cultured without the inhibitor. We investigated the mechanism underlying the differential responses of differentiating eosinophils and their functionalities in response to eosinophil-active cytokines in the presence and absence of GSI. UCB cells cultured for 4 weeks with hematopoietic cytokines in the presence or absence of GSI were monitored for extracellular signal-regulated kinase (ERK) phosphorylation, MBP expression, and functionality. Eosinophil differentiation from UCB cells was accompanied by activation of the ERK1/2 pathway during the 4-week culture period. In particular, strong ERK1/2 phosphorylation was observed in eosinophils during the final stage of culture when GSI was present. Consistent with this finding, ERK inhibition nullified the effect of GSI on eosinophil differentiation. Eosinophils cultured with GSI resembled airway eosinophils rather than peripheral blood eosinophils based on reduced IL-5Ralpha expression, blunted eosinophil cationic protein (ECP) degranulation, and decreased IL-13 and granulocyte macrophage-colony-stimulating factor production. These results suggest that Notch signaling regulates the terminal differentiation and subsequent effector phenotypes of eosinophils, partly through modulation of the ERK pathway. GSI has therapeutic potential for eosinophilic inflammatory diseases, such as asthma.
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PMID:Regulation of functional phenotypes of cord blood derived eosinophils by gamma-secretase inhibitor. 1760 Mar 16

The ontogeny of the C-C chemokines eotaxin-1, eotaxin-2, and eotaxin-3 has not been fully elucidated in human lung. We explored a possible role for eotaxin in developing lung by determining the ontogeny of eotaxin-1 (CCL11), eotaxin-2 (CCL24), eotaxin-3 (CCL26), and the eotaxin receptor, CCR3. We tested discarded surgical samples of developing human lung tissue using quantitative RT-PCR (QRT-PCR) and immunostaining for expression of CCL11, CCL24, CCL26, and CCR3. We assessed possible functionality of the eotaxin-CCR3 system by treating lung explant cultures with exogenous CCL11 and analyzing the cultures for evidence of changes in proliferation and activation of ERK1/2, a signaling pathway associated with CCR3. QRT-PCR analyses of 22 developing lung tissue samples with gestational ages 10-23 wk demonstrated that eotaxin-1 mRNA is most abundant in developing lung, whereas mRNAs for eotaxin-2 and eotaxin-3 are minimally detectable. CCL11 mRNA levels correlated with gestational age (P < 0.05), and immunoreactivity was localized predominantly to airway epithelial cells. QRT-PCR analysis detected CCR3 expression in 16 of 19 developing lung samples. Supporting functional capacity in the immature lung, CCL11 treatment of lung explant cultures resulted in significantly increased (P < 0.05) cell proliferation and activation of the ERK signaling pathway, which is downstream from CCR3, suggesting that proliferation was due to activation of CCR3 receptors by CCL11. We conclude that developing lung expresses the eotaxins and functional CCR3 receptor. CCL11 may promote airway epithelial proliferation in the developing lung.
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PMID:Ontogeny of the eotaxins in human lung. 1805 44

Inappropriately activated eosinophils can contribute to disease pathogenesis and intracellular signalling pathways that regulate functional responses may represent a therapeutic target. Little is known about intracellular signalling in equine eosinophils and this study examined the role of phospholipase C (PLC) and a range of protein kinases on responses to histamine and CCL11. Histamine (10(-4) M) or CCL11 (5.6 x 10(-9) M)-induced actin polymerization, migration and superoxide production by eosinophils from healthy horses were compared in the presence and absence of selective kinase inhibitors. Inhibition of phosphatidylinositol-3 kinase (PI3K) significantly reduced the response in each assay. In contrast, whilst inhibition of PLC decreased actin polymerization and superoxide production, an increase in migration was observed; the latter effect was also seen when protein kinase C (PKC) was inhibited. With the exception of histamine-induced migration, which was significantly reduced by blocking extracellular regulated kinase (ERK)1/2, activation of ERK1/2, p38 MAPK and tyrosine kinase did not appear to play an important role in the responses studied. These results suggest that equine eosinophil activation by histamine and CCL11 is mediated through PI3K. Whilst PLC activation is required for actin polymerization and superoxide production, migration may be negatively regulated by PLC and PKC. These kinases represent potential targets for modulating eosinophil activation by multiple stimuli.
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PMID:Role of intracellular kinases in the regulation of equine eosinophil migration and actin polymerization. 1817 16

High-content screening, typically defined as automated fluorescence microscopy combined with image analysis, is now well established as a means to study test compound effects in cellular disease-modeling systems. In this work, the authors establish several high-content screening assays in the 384-well format to measure the activation of the CC-type chemokine receptors 2B and 3 (CCR2B, CCR3). As a cellular model system, the authors use Chinese hamster ovary cells, stably transfected with 1 of the respective receptors. They characterize receptor stimulation by human monocyte chemoattractant protein-1 for CCR2B and by human eotaxin-1 for CCR3: Receptor internalization and receptor-induced phosphorylation of ERK1/2 (pERK) were quantified using fluorescence imaging and image analysis. The 4 assay formats were robust, displayed little day-to-day variability, and delivered good Z' statistics for both CCRs. For each of the 2 receptors, the authors evaluated the potency of inhibitory compounds in the internalization format and the pERK assay and compared the results with those from other assays (ligand displacement binding, Ca(2+) mobilization, guanosine triphosphate exchange, chemotaxis). Both physiological agonists and test compounds differed significantly with respect to potencies and efficacies in the various profiling assays. The diverse assay formats delivered partially overlapping and partially complementary information, enabling the authors to reduce the probability of test compound-related technology artifacts and to specify the mode of action for individual test compounds. Transfer of the high-content screening format to a fully automated medium-throughput screening platform for CCR3 enabled the profiling of large compound numbers with respect to G protein signaling and possible tolerance-inducing liabilities.
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PMID:Pharmacological profiling of chemokine receptor-directed compounds using high-content screening. 1822 25

The accumulation of eosinophils in inflammatory foci is a hallmark characteristic of Th2 inflammation. Nevertheless, the expression of inhibitory receptors such as paired immunoglobulin-like receptor B (PIR-B) and their function regulating eosinophil accumulation have received limited attention. We now report that Pirb was up-regulated in an eosinophil-dependent manner in the lungs of allergen-challenged and interleukin (IL)-13-overexpressing mice. Eosinophils expressed high levels of PIR-B, and Pirb(-/-) mice displayed increased gastrointestinal eosinophils. Consistent with these findings, PIR-B negatively regulated eotaxin-dependent eosinophil chemotaxis in vivo and in vitro. Surprisingly, Pirb(-/-) eosinophils and neutrophils had decreased leukotriene B4 (LTB(4))-dependent chemotactic responses in vitro. Furthermore, eosinophil accumulation was decreased in a chitin-induced model, partially dependent on LTB(4). Mechanistic analysis using a miniphosphoproteomic approach revealed that PIR-B recruits activating kinases after LTB(4) but not eotaxin stimulation. Consequently, eotaxin-activated Pirb(-/-) eosinophils displayed markedly increased extracellular signal-related kinase 1 and 2 (ERK1/2) phosphorylation, whereas LTB(4)-activated eosinophils had reduced ERK1/2 phosphorylation. We provide multiple lines of evidence supporting a model in which PIR-B displays opposing but potent regulatory functions in granulocyte activation. These data change the conventional wisdom that inhibitory receptors are restricted to inhibitory signals; we therefore propose that a single receptor can have dual functionality in distinct cell types after unique cellular signals.
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PMID:A dual activation and inhibition role for the paired immunoglobulin-like receptor B in eosinophils. 1854 94

The differential usage of signaling pathways by chemokines and cytokines in eosinophils is largely unresolved. In this study, we investigate signaling similarities and differences between CCL11 (eotaxin) and IL-5 in a phosphosite screen of human eosinophils. We confirm many previously known pathways of cytokine and chemokine signaling and elucidate novel phosphoregulation in eosinophils. The signaling molecules that were stimulated by both agents were members of the ERK1/2 and p38 MAPK pathways and their downstream effectors such as RSK and MSK1/2. Both agents inhibited S6 kinase, protein kinase Cepsilon, and glycogen synthase kinase 3 alpha and beta. The molecules that were differentially regulated include STATs and protein kinase R (PKR). One of the chief findings in this investigation was that PKR and eukaryotic initiation factor 2alpha are phosphorylated under basal conditions in eosinophils and neutrophils. This basal phosphorylation was linked to autocrine secretion of TGF-beta in eosinophils. TGF-beta directly activates PKR in eosinophils. Basal phosphorylation of PKR was inhibited by incubation of eosinophils with a neutralizing anti-TGF-beta Ab suggesting its physiological importance. We show that inhibition of PKR activity prolongs eosinophil survival. The eosinophil survival factor IL-5 strongly suppresses phosphorylation of PKR. The biological relevance of IL-5 inhibition of phospho-PKR was established by the observation that ex vivo bone marrow-derived eosinophils from OVA-immunized mice had no PKR phosphorylation in contrast to the high level of phosphorylation in sham-immunized mice. Together, our findings suggest that survival of eosinophils is in part controlled by basal activation of PKR through autocrine TGF-beta and that this could be modulated by a Th2 microenvironment in vivo.
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PMID:A phosphosite screen identifies autocrine TGF-beta-driven activation of protein kinase R as a survival-limiting factor for eosinophils. 1832 38

Diesel exhaust particles (DEPs), comprised mainly of particles less than 2.5 microm (PM 2.5) in aerodynamic diameter, have been assumed to enhance the response of asthma to allergen inhalation. Although eosinophilic infiltration is remarkable in the event of bronchial asthma induced by DEPs, the precise mechanisms leading to eosinophilia are unknown. To examine the effect of DEPs on eosinophils, we measured the cytokine products and activity of nuclear factor-kappa B (NF-kappa B) after addition of the proteasomal inhibitor MG132 in HL-60 clone 15 cells differentiated into eosinophils. We measured eotaxin-induced chemotaxis of cells and their activity of p38 mitogen-activated protein (MAP) kinase was analysed. Interleukin (IL)-8 and monocyte chemoattractant protein-1 (MCP-1) were increased markedly in DEPs-treated cells. The active form of NF-kappaB in cells treated with DEPs was increased, and this effect was significantly decreased by the administration of MG132. Cell migration in the presence of DEPs was significantly greater, and inhibited by adding N-acetyl l-cysteine. P38 MAP kinase activity was highly influenced by DEPs-treatment. DEPs induce MCP-1 and IL-8 production by up-regulating NF-kappa B activity, which is inhibited in the presence of an inhibitor of proteasomal degradation. DEP also promotes eotaxin-induced chemotaxis in a p38-dependent manner.
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PMID:In vitro toxicity evaluation of diesel exhaust particles on human eosinophilic cell. 1835 85

Oncostatin M (OSM) is an IL-6/LIF cytokine family member whose role has been identified in a range of biological activities in vitro, including upregulation of inflammatory gene expression and regulation of connective tissue metabolism. Previously, we identified murine OSM (mOSM) as an inducer of the eosinophil-chemoattractant protein eotaxin-1, both in vitro using fibroblast cell lines and in vivo from mouse lung tissues. Using the NIH 3T3 cell line, we demonstrate the requirement of PI3'K activation for mOSM induction of eotaxin-1 through inhibition of both mOSM-stimulated mRNA and protein expression using the PI3'K antagonist LY294002. By assessment of phosphorylation of the downstream mediator Akt, we show mOSM to be differentially capable of activating PI3'K relative to the related gp130-utilizing cytokine IL-6. Assessment of eotaxin-1 gene expression utilizing PKB/Akt mutant-transfected NIH 3T3 cell lines demonstrated Akt is not involved in upstream regulation of eotaxin-1 through mOSM, indicating an alternate kinase pathway downstream of PI3'K may be involved. We demonstrate that mOSM stimulation of expression of eotaxin-1 is reduced by PD98059, a MAPK kinase inhibitor selective for MEK1. Both LY294002 and PD98059 attenuated mOSM-induced phosphorylation of ERK1/2 MAP kinase and also reduced binding of an AP-1 responsive promoter element, a transcriptional complex known to be MAPK-sensitive. Further, LY294002 pretreatment reduced mOSM-stimulated expression of the downstream AP-1 co-factor JunB, while PD98059 reduced levels of JunB as well as c-Fos. These results provide evidence for a previously unidentified signaling mechanism utilized by mOSM for the induction of eotaxin-1.
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PMID:Oncostatin M induction of eotaxin-1 expression requires the convergence of PI3'K and ERK1/2 MAPK signal transduction pathways. 1837 59

Resistin-like molecule alpha (Relm-alpha) is a secreted cysteine-rich protein belonging to a newly defined family of proteins, including resistin, Relm-beta, and Relm-gamma. Resistin was initially defined based on its insulin resistance activity, but the family members are highly up-regulated in various inflammatory states, especially those involving intestinal inflammation. In this study, we report the role of Relm-alpha at baseline and following an experimental model of colitis. Relm-alpha was readily detected in the serum at baseline (4-5 ng/ml), and its level was regulated by energy uptake. Retnla(-/-) mice had decreased baseline circulating leptin levels, but displayed normal glucose, glucose clearance, and insulin levels. Following exposure to the oral innate trigger dextran sodium sulfate (DSS), a nonredundant proinflammatory role for Relm-alpha was uncovered as Retnla(-/-) mice were markedly protected from DSS-induced disease activity and histopathological features. Relm-alpha regulated eosinophil-directed cytokines (e.g., IL-5, CCL11/eotaxin-1, and CCL5/RANTES) and IL-17 ex vivo. Consistently, DSS-treated Retnla(-/-) mice displayed substantially decreased eosinophil accumulation and decreased phosphorylation of NF-kappaB, ERK1/2, and p38 in macrophages and eosinophils. Following DSS exposure, serum level of Relm-alpha was up-regulated, and DSS-treated Retnla(-/-) mice were markedly protected from hyperglycemia induced by glucose injection independent of changes in insulin levels. Retnla(-/-) mice were protected from increases in gut hormone serum levels of gastric inhibitory polypeptide and peptide YY that were induced following DSS treatment. These findings demonstrate a central proinflammatory role for Relm-alpha in the regulation of colonic inflammation and a novel link between colonic injury, glucose tolerance, and energy intake.
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PMID:Resistin-like molecule alpha decreases glucose tolerance during intestinal inflammation. 1920 90


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