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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role intestinal epithelial cells play in the pathogenesis of amebic colitis is poorly understood. Herein, we demonstrate that secreted and soluble ameba (Entamoeba histolytica) proteins (SAP) induce expression of the chemoattractant monocyte chemotactic protein (MCP) in the colonic epithelial cell lines Caco-2, T84, and LS174T. MCP-1 mRNA induction was both dose and time dependent, with peak induction occurring at 8 h and with 100 mug/ml of SAP. Significant increase in MCP-1 protein expression was observed after 12 h. SAP failed to activate any of the mitogen-activated protein kinase pathways or IkappaB kinase activity. Moreover, inhibiting the classical pathway of NF-kappaB activation did not affect SAP-induced MCP-1 expression. Instead, we find that SAP-induced MCP-1 expression is dependent on posttranslational modification of the NFkappaB p65 subunit. SAP induced phosphorylation of p65 and enhanced NF-kappaB transcriptional activity, which are phosphatidylinositol 3-kinase (PI3 kinase) dependent. Treatment with PI3 kinase inhibitor LY290004 significantly abrogated the activation of Akt, p65, and MCP-1 mRNA induction. We conclude that colonic epithelial cells play a role in the initiation of inflammation by secreting chemokines in response to soluble ameba components.
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PMID:Induction of monocyte chemotactic protein 1 in colonic epithelial cells by Entamoeba histolytica is mediated via the phosphatidylinositol 3-kinase/p65 pathway. 1728 5

The blood brain barrier (BBB) is composed of specialized endothelial cells tightly anastomosed to one another and surrounded by a thick extracellular matrix, the basement membrane. Together these components restrict the diffusion of cells and molecules from the periphery into the central nervous system (CNS), providing immune privilege and homeostasis. Dysregulation of the BBB and trans-endothelial migration of immune cells are amongst the earliest CNS changes partaking in lesion formation in multiple sclerosis (MS). Death receptors are members of the tumor necrosis factor receptor (TNFR) super-family. They are expressed on a variety of tissues including endothelium, but the consequence of their triggering appears to be cell type specific. In this study, we describe the expression of death receptors TNFR1, Fas and DR5 on primary cultures of human BBB-derived endothelial cells (ECs), as well as the effects of receptor activation on human brain endothelial cell (HBEC) function. We show that HBECs are resistant to cell death mediated via TNFalpha, FasL and TRAIL and that neither receptor ligation induces cellular proliferation of HBECs. TNFR1 ligation induces NFkappaB activation and the upregulation of chemokines MCP-1 and IL-8, as well as adhesion molecules ICAM-1 and VCAM-1, while Fas and DR5 triggering activate the extracellular signal regulated kinases-1 and -2 (Erk 1/2, p42/44 MAPK) inducing the release of matrix metalloproteinase 9 (MMP9) by BBB-derived ECs.
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PMID:Death receptor expression and function at the human blood brain barrier. 1739 9

To investigate the modulation of lung local immune responses of hesperidin (HES) on the acute lung inflammation induced by LPS in vivo. Mice were challenged with intratracheal lipopolysaccharide (100 microg) 30 min before with treatment hesperidin (200 mg/kg oral administration) or vehicle. After 4 and 24 h, bronchoalveolar lavage fluid was obtained to measure proinflammatory (TNF-alpha, IL-1 beta, IL-6), anti-inflammatory (IL-10, IL-4, IL-12) cytokines, chemokines (KC, MCP-1 and MIP-2), total cell counts, nitric oxide production, and proteins. Lung histology was performed in inflated-fixed lungs. Hesperidin downregulate the LPS-induced expression of TNF-alpha, IL-1 beta, IL-6, KC, MIP-2, MCP-1, and IL-12. It also enhanced the production of IL-4, IL-10. Total leukocyte counts; nitric oxide production, iNOS expression, and proteins were significantly decreased by hesperidin. In vitro, HES suppressed the expression of IL-8 on A549 cells and THP-1 cells, the expression of TNF-alpha, IL-1 beta, and IL-6 on THP-1 cells, the expression of ICAM-1 and VCAM-1 on A549 cells which effect cell adhesion function. The suppression of those molecules is controlled by NF-kappaB and AP-1, which are activated by I kappa B and MAPK pathways. HES inhibits those pathways, thereby suppressing the expression of IL-8, TNFalpha, IL-1 beta, IL-6, IL-12, ICAM-1 and VCAM-1. This study indicates that HES had a markedly immunomodulatory effect in a clinically relevant model of ARDS. Nevertheless, further investigations are required to determine the potential clinical usefulness of HES in the adjunctive therapy of ARDS.
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PMID:The immunomodulation of endotoxin-induced acute lung injury by hesperidin in vivo and in vitro. 1740 Feb 56

The chemokine receptor CXCR4, which binds the chemokine stromal cell-derived factor 1, has been reported to be involved in the chemotaxis of inflammatory cells. In addition, AMD3100, an antagonist of CXCR4, has been reported to be an attractive drug candidate for therapeutic intervention in several disorders in which CXCR4 is critically involved. However, little is known about the therapeutic value of AMD3100 in the treatment of pulmonary fibrosis. In this study, we examined the effects of AMD3100 on a murine bleomycin-induced pulmonary fibrosis model. Concurrent administration of AMD3100 and bleomycin apparently attenuated bleomycin-induced pulmonary inflammation. In this process, an inhibition of neutrophil recruitment at early stage followed by the decrease of other inflammatory cell recruitment in the lung were observed. In addition, it also inhibited the expression of cytokines, including MCP-1, MIP-2, MIP-1alpha, and TGF-beta. In contrast, when AMD3100 was administered following bleomycin treatment, the bleomycin-induced lung inflammation progressed and resulted in severe pulmonary fibrosis. In this process, an increase of inflammatory cell recruitment, an up-regulation of lung MCP-1 and TGF-beta, and a remarkable activation of p44/42 MAPK in neutrophils were observed. U0126, an inhibitor of p44/42 MAPK, significantly abolished these effects. Thus, AMD3100 has dual effect on bleomycin-induced pulmonary fibrosis. Difference of inflammatory cell recruitment and activation might be associated with the dual effect of AMD3100 on bleomycin-induced pulmonary fibrosis.
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PMID:Dual effect of AMD3100, a CXCR4 antagonist, on bleomycin-induced lung inflammation. 1894 Dec 58

9-cis-Retinoic acid (9CRA) plays an important role in the immune response; this includes cytokine production and cell migration. We have previously demonstrated that 9CRA increases expression of chemokine receptors CCR1 and CCR2 in human monocytes. To better understand how 9CRA induces CCR1 and CCR2 expression, we examined the contribution of signaling proteins in human monocytic THP-1 cells. The mRNA and surface protein up-regulation of CCR1 and CCR2 in 9CRA-stimulated cells were weakly blocked by the pretreatment of SB202190, a p38 MAPK inhibitor, and PD98059, an upstream ERK inhibitor. Activation of p38 MAPK and ERK1/2 was induced in both a time and dose-dependent manner after 9CRA stimulation. Both p38 MAPK and ERK1/2 phosphorylation peaked at 2 h after a 100 nM 9CRA treatment. 9CRA increased calcium influx and chemotactic activity in response to CCR1-dependent chemokines, Lkn-1/CCL15, MIP-1alpha/CCL3, and RANTES/CCL5, and the CCR2-specific chemokine, MCP-1/CCL2. Both SB202190 and PD98059 pretreatment diminished the increased calcium mobilization and chemotactic ability due to 9CRA. SB202190 inhibited the expression and functional activities of CCR1 and CCR2 more effectively than did PD98059. Therefore, our results demonstrate that 9CRA transduces the signal through p38 MAPK and ERK1/2 for CCR1 and CCR2 up-regulation, and may regulate the pro-inflammatory process through the p38 MAPK and ERK-dependent signaling pathways.
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PMID:p38 MAPK and ERK activation by 9-cis-retinoic acid induces chemokine receptors CCR1 and CCR2 expression in human monocytic THP-1 cells. 1746 74

Pancreatic and lung inflammation during acute pancreatitis is a poorly understood, but clinically important, phenomenon. The proto-oncogene Tpl2 (tumor progression locus-2) has recently been shown to have important immunomodulatory effects on some inflammatory processes, but its importance to pancreatitis has not been previously examined. Our studies were designed to (a) define the effects of Tpl2 on pancreatic and lung inflammation during pancreatitis and (b) identify mechanisms and cell types responsible for those effects. We examined pancreatitis-associated Tpl2 effects in wild type and Tpl2(-/-) mice subjected to either secretagogue-induced or bile salt-induced pancreatitis. To determine the myeloid or non-myeloid lineage of cells responsible for the Tpl2 effects, we used Tpl2(-/-) chimeric mice generated by lethal irradiation followed by bone marrow transplantation. Mechanisms responsible for the effects of Tpl2 ablation on caerulein-induced proinflammatory events were evaluated under in vivo and in vitro conditions using the techniques of electrophoretic mobility shift assay, immunoblot analysis, and quantitative reverse transcription-PCR. We found that Tpl2 ablation markedly reduced pancreatic and lung inflammation in these two dissimilar models of pancreatitis, but it did not alter pancreatic injury/necrosis in either model. The reduction in caerulein-induced pancreatic inflammation is dependent upon Tpl2 ablation in non-myeloid cells and is associated with both in vivo and in vitro inhibition of MEK, JNK, and AP-1 activation and the expression of MCP-1, MIP-2, and interleukin-6. Non-myeloid cell expression of Tpl2 regulates pancreatic inflammation during pancreatitis by mediating proinflammatory signals and the generation of neutrophil chemoattracting factors.
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PMID:Tumor progression locus-2 is a critical regulator of pancreatic and lung inflammation during acute pancreatitis. 1753 24

Recent reports indicated that vascular remodeling and angiogenesis are promoted by conditioned medium from the cells referred to as multipotent stromal cells (MSCs). However, the molecular events triggered by MSC-conditioned medium (CdM) were not defined. We examined the effects of CdM from human MSCs on cultures of primary human aortic endothelial cells (HAECs). The CdM inhibited hypoxia-induced apoptosis and cell death of HAECs. It also promoted tube formation by HAECs in an assay in vitro. Conditioned medium from multipotent stromal cells incubated under hypoxic conditions in serum-free endothelial basal medium for 2 days (CdM(Hyp)) from hypoxic culture of MSCs was more effective than conditioned medium from MSCs incubated under normoxic conditions in serum-free endothelial basal medium for 2 days from normoxic cultures of MSCs, an observation in part explained by its higher content of antiapoptotic and angiogenic factors, such as interleukin (IL)-6, vascular endothelial growth factor (VEGF), and monocyte chemoattractant protein (MCP)-1. The effects of CdM(Hyp) on hypoxic HAECs were partially duplicated by the addition of IL-6 in a dose-dependent manner; however, anti-IL-6, anti-MCP-1, and anti-VEGF blocking antibodies added independently did not attenuate the effects. Also, addition of CdM(Hyp) activated the PI3K-Akt pathway; the levels of p-Akt and several of its downstream targets were increased by CdM(Hyp), and both the increase in p-Akt and the increase in angiogenesis were blocked by an inhibitor of PI3K-Akt or by expression of a dominant negative gene for PI3K. CdM(Hyp) also increased the levels of p-extracellular signal-regulated kinase (ERK), but there was a minimal effect on p-signal transducer and activator of transcription-3, and an inhibitor of the ERK1/2 pathway had no effect on hypoxia-induced apoptosis of the HAECs. The results are consistent with suggestions that administration of MSCs or factors secreted by MSCs may provide a therapeutic method of decreasing apoptosis and enhancing angiogenesis.
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PMID:Angiogenic effects of human multipotent stromal cell conditioned medium activate the PI3K-Akt pathway in hypoxic endothelial cells to inhibit apoptosis, increase survival, and stimulate angiogenesis. 1754 Aug 57

Interleukin-31 (IL-31) is a novel T-helper-lymphocyte-derived cytokine that plays an important role in allergic skin inflammation and atopic dermatitis. It has recently been implicated in bronchial inflammation. We investigated the functions and mechanisms of IL-31-induced activation of human bronchial epithelial cells. The gene and protein expressions of candidate cytokines/chemokines from IL-31-stimulated human bronchial epithelial BEAS-2B cells were first quantified by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The activity of different mitogen-activated protein kinases (MAPKs) in IL-31-stimulated BEAS-2B cells was assessed by Western blot. The IL-31 could significantly elevate the gene and protein expressions of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1/CCL2) of BEAS-2B cells in both time-dependently and dose-dependently. Combination of IL-31 with either IL-4 or IL-13 further enhanced VEGF and CCL2 production while IL-31 could synergistically augment the release of EGF, VEGF, CCL2, IL-6 and IL-8 in cocultures of BEAS-2B cells and eosinophils. In addition, IL-31 could activate p38 MAPK, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) of BEAS-2B cells. Selective inhibitors of p38 MAPK (SB203580), ERK (PD98059), and JNK (SP600125) could differentially inhibit the production of EGF, VEGF and CCL2, thereby suggesting a role for MAPKs in IL-31 functions. In conclusion, the activation of MAPKs can be crucial for IL-31-mediated activation of bronchial epithelial cells, thereby providing an immunological role for IL-31 in bronchial inflammation, at least partly, via epithelial EGF, VEGF and CCL2 production.
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PMID:Interleukin-31 induces cytokine and chemokine production from human bronchial epithelial cells through activation of mitogen-activated protein kinase signalling pathways: implications for the allergic response. 1762 70

Leptin is a pleiotropic adipocyte-derived cytokine used in hypothalamic regulation of body weight and modulation of immune response by stimulating T cells, macrophages and neutrophils. Leptin has been shown to be an eosinophil survival factor. We examined the immunopathological mechanisms for the activation of human eosinophils from healthy volunteers by leptin in allergic inflammation. Adhesion molecules, cytokines and cell migration were assessed by flow cytometry, ELISA and Boyden chamber assay, respectively. Intracellular signaling molecules were investigated by membrane array and Western blot. Leptin could up-regulate cell surface expression of adhesion molecule ICAM-1 and CD18 but suppress ICAM-3 and L-selectin on eosinophils. Leptin could also stimulate the chemokinesis of eosinophils, and induce the release of inflammatory cytokines IL-1beta and IL-6, and chemokines IL-8, growth-related oncogene-alpha and MCP-1. We found that leptin-mediated induction of adhesion molecules, release of cytokines and chemokines, and chemokinesis were differentially regulated by the activation of ERK, p38 MAPK and NF-kappaB. In view of the above results and elevated production of leptin in patients with allergic diseases such as atopic asthma and atopic dermatitis, leptin could play crucial immunopathophysiological roles in allergic inflammation by activation of eosinophils via differential intracellular signaling cascades.
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PMID:Leptin-mediated cytokine release and migration of eosinophils: implications for immunopathophysiology of allergic inflammation. 1763 54

TLRs are key elements of the pathogen recognition mechanism used by the host immune system. Neutrophils express almost all TLRs, and activation of TLRs, such as TLR2 and TLR4, has been shown to induce the production of proinflammatory cytokines and chemokines, potentially linking innate and adaptive immunity. In the present study, we investigated whether activation of TLRs induces neutrophil production of MCP-1/CCL2, a key mediator involved in the development of adaptive immunity. Activation of neutrophils with LPS, lipoteichoic acid, or N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-[R]-Cys-[S]-Ser-[S]-Lys did not induce significant MCP-1 production and release; however, the Th1 cytokine IFN-gamma dramatically up-regulated MCP-1 production in cells activated with each TLR ligand. The majority of MCP-1 was released between 24 and 48 h of culture, indicating that this is a late event. The effect of IFN-gamma appeared to be due to its antiapoptotic effect, but not priming effect, revealing a biological consequence of IFN-gamma-induced neutrophil survival. Although IFN-gamma failed to protect neutrophils from cell death at a higher dose of LPS, the p38 MAPK inhibitor SB203580 dramatically increased MCP-1 release and neutrophil survival at this LPS concentration. Thus, p38 MAPK plays a previously uncharacterized role in neutrophil function. Taken together, our results indicate that human neutrophils produce MCP-1 in a Th1 microenvironment and this neutrophil-derived MCP-1 potentially amplifies the development of Th1 adaptive responses.
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PMID:IFN-gamma-mediated survival enables human neutrophils to produce MCP-1/CCL2 in response to activation by TLR ligands. 1764 Oct 61


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