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)

CXCL8 is a chemokine that is implicated in the formation of tuberculous (TB) granulomas and in immunity to Mycobacterium tuberculosis (Mtb). Fibroblast chemokine secretion is important for modulating inflammatory responses in chronic lung disease and inflammatory arthritis but has not been investigated in the pathophysiology of TB. In this study, we used a cellular model to examine monocyte/macrophage-dependent stimulation of fibroblasts by Mtb in the regulation of chemokine secretion, particularly that of CXCL8. Human lung fibroblasts grown in collagen were stimulated with conditioned medium from Mtb-infected monocytes (CoMTb). CoMTb-induced prolonged dose-dependent, p38-mediated expression of stable CXCL8 mRNA by fibroblasts accompanied by a >10-fold increase in CXCL8 secretion (487 +/- 88 ng/ml vs 48.6 +/- 34 ng/ml in controls) at 120 h. Fibroblasts strongly expressed CXCL8 in vivo in human TB granulomas. Inhibition of TNF-alpha or IL-1 in CoMTb abrogated the induction of CXCL8 at a pretranscriptional level. CXCL8 secretion was NF-kappaB, C/EBP, and JNK dependent. Sustained NF-kappaB activation was demonstrated beyond 24 h in response to CoMTb. Exogenous CXCL8 reduced the survival of Mtb within macrophages, and inhibition of CXCL8 was associated with intracellular mycobacterial proliferation. These data show that fibroblasts have a previously unrecognized role in modulating inflammation in TB by their CXCL8-dependent contribution to cell recruitment and mycobacterial killing within the granuloma.
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PMID:Monocyte-dependent fibroblast CXCL8 secretion occurs in tuberculosis and limits survival of mycobacteria within macrophages. 1733 75

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with progressive airflow obstruction. Tobacco smoking is the main risk factor worldwide. In contrast to asthma, antiinflammatory therapies are rather ineffective in improving chronic symptoms and reducing inflammation, lung function decline, and airway remodeling. Specific drugs that are directed against the remodeling and chronic inflammation, thereby preventing lung tissue damage and progressive lung function decline, must be developed. Experimental models and expression studies suggest that anti-vascular endothelial growth factor (VEGF) receptor strategies may be of use in patients with emphysema, whereas anti-HER1-directed strategies may be more useful in patients with pulmonary mucus hypersecretion, as seen in chronic bronchitis and asthma. Growth factors and cytokines including VEGF, fibroblast growth factors, transforming growth factor-beta, tumor necrosis factor-alpha, CXCL1, CXCL8, and CCL2, and signal transduction proteins such as mitogen-activated protein kinase p38 and nuclear factor-kappaB, seem to be important pathogenetic molecules in COPD. Specific antagonists for these proteins may be effective for different inflammatory diseases. However, their efficacy for COPD therapy has not yet been demonstrated. Finally, other drugs such as retinoic acids may provide restoration of lung tissue structure. Such approaches, however, must await the first results of growth factor or cytokine antagonist therapy in chronic lung diseases.
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PMID:Molecular mechanisms in chronic obstructive pulmonary disease: potential targets for therapy. 1740 66

Both angiotensin II (ANG II) and transforming growth factor-beta1 (TGF-beta1) are thought to be involved in mediating pulmonary fibrosis. Interactions between the renin-angiotensin system (RAS) and TGF-beta1 have been well documented, with most studies describing the effect of ANG II on TGF-beta1 expression. However, recent gene expression profiling experiments demonstrated that the angiotensin II type 1 receptor (AT(1)R) gene was a novel TGF-beta1 target in human adult lung fibroblasts. In this report, we show that TGF-beta1 augments human AT(1)R (hAT(1)R) steady-state mRNA and protein levels in a dose- and time-dependent manner in primary human fetal pulmonary fibroblasts (hPFBs). Nuclear run-on experiments demonstrate that TGF-beta1 transcriptionally activates the hAT(1)R gene and does not influence hAT(1)R mRNA stability. Pharmacological inhibitors and specific siRNA knockdown experiments demonstrate that the TGF-beta1 type 1 receptor (TbetaRI/ALK5), Smad2/3, and Smad4 are essential for TGF-beta1-stimulated hAT(1)R expression. Additional pharmacological inhibitor and small interference RNA experiments also demonstrated that p38 MAPK, JNK, and phosphatidylinositol 3-kinase (PI3K) signaling pathways are also involved in the TGF-beta1-stimulated increase in hAT(1)R density. Together, our results suggest an important role for cross talk among Smad, p38 MAPK, JNK, and PI3K pathways in mediating the augmented expression of hAT(1)R following TGF-beta1 treatment in hPFB. This study supports the hypothesis that a self-potentiating loop exists between the RAS and the TGF-beta1 signaling pathways and suggests that ANG II and TGF-beta1 may cooperate in the pathogenesis of pulmonary fibrosis. The synergy between these systems may require that both pathways be simultaneously inhibited to treat fibrotic lung disease.
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PMID:TGF-beta1 stimulates human AT1 receptor expression in lung fibroblasts by cross talk between the Smad, p38 MAPK, JNK, and PI3K signaling pathways. 2336 40

Oxidant stress plays a role in the pathogenesis of pulmonary diseases, including fibrotic lung disease and cancer. We previously found that hydrogen peroxide (H2O2) initiates an increase in Ca2+/cAMP-response element binding protein (CREB) phosphorylation in C10 alveolar type II cells that requires activation of extracellular regulated kinases 1/2 (ERK1/2). Here, we investigated the role of crosstalk between protein kinase A (PKA) and epidermal growth factor receptor (EGFR) in oxidant-induced signaling to ERK1/2 and CREB in C10 cells. Application of H2O2 increased nuclear accumulation of PKA, and inhibition of PKA with H89 reduced oxidant-mediated phosphorylation of both CREB and ERK1/2. Single cell measurements of cAMP and redox status, using a FRET-based biosensor and a redox-sensitive GFP, respectively, indicated that H2O2 increases production of cAMP that correlates with redox state. Inhibition of EGFR activity decreased both H2O2-induced CREB phosphorylation and translocation of PKA to the nucleus, suggesting that crosstalk between PKA and EGFR underlies the oxidant-induced CREB response. Furthermore, knockdown of CREB expression using siRNA led to a decrease in bcl-2 and an increase in oxidant-induced apoptosis. Together these data reveal a novel role for crosstalk between PKA, ERK1/2 and CREB that mediates cell survival during oxidant stress.
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PMID:Protein kinase A-mediated CREB phosphorylation is an oxidant-induced survival pathway in alveolar type II cells. 1839 38

Gene delivery applications to treat lung diseases are, in some instances, suboptimal due to deleterious host inflammatory reactions. Current DNA plasmids (pDNA) exert toxicity in part via unmethylated CpG motifs that stimulate Toll-like receptor (TLR)9-expressing leukocytes; however, the airway epithelial response has not been well defined. Bronchial epithelial cells (BEAS-2B) were exposed to pDNA complexes and inflammatory mediators were measured. As patients with inflammatory lung disease are susceptible to infectious exacerbations, we also evaluated the reciprocal inflammatory response to pDNA and bacterial components lipopolysaccharide (LPS) and lipoteichoic acid (LTA), recognized by TLR4 and TLR2, respectively. Cells primed with pDNA synergistically expressed IL-8 mRNA and protein in response to LPS and LTA (3- to 5-fold). A similar induction was also observed for IL-1beta, IL-6, colony-stimulating factor (CSF)-1, and granulocyte macrophage-CSF. Their synergistic elevation was associated with an increase in TLR4 and TLR2 levels. Methylation of pDNA only partially reduced (25-30%) IL-8 release; hence, signaling occurs via CpG/TLR9-dependent and -independent modules. As epidermal growth factor receptor (EGFR) signaling has been implicated in bronchial IL-8 expression, we assessed whether pDNA priming events were coordinated via EGFR. AG1478 (EGFR inhibitor) restored normal TLR4/2 levels and also suppressed synergistic release of IL-8. The extracellular signal-regulated kinase (Erk) mitogen-activated protein kinase inhibitor also blocked IL-8 release, implicating Erk as a key mediator of EGFR signaling. Our findings identify a novel EGFR-dependent mechanism for regulating TLR, and show that targeted disruption of EGFR signaling ameliorates the airway epithelial inflammatory response to pDNA. Targeting the EGFR system may improve the efficiency, tolerability, and safety of gene therapy strategies.
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PMID:DNA vector augments inflammation in epithelial cells via EGFR-dependent regulation of TLR4 and TLR2. 1840 79

Mycobacterium avium (MAV) and M. abscessus (MAB) are ubiquitous environmental organisms increasingly recognized to cause chronic lung disease in patients with apparently normal immune function. Little is yet known about their human pathophysiology. Our objective was to examine cytokine and chemokine responses (protein and gene expression) and signaling pathways triggered by reference and clinical isolates of MAB and MAV in human peripheral blood mononuclear cells, monocytes, and murine bone marrow-derived macrophages in vitro. MAB-induced TNF-alpha production was higher than that induced by MAV. IFN-gamma, IL-1beta, and the chemokines macrophage inflammatory protein-1alpha and regulated on activation, normal T cell expressed and secreted were equally up-regulated. Differences between MAB and MAV do not require replication and are heat stable. We found no differential effect due to rough or smooth colonies within the same species. Similar to MAV, MAB triggered mitogen-activated protein kinase (MAPK) signaling and nuclear factor-kappaB translocation. Induction of TNF-alpha was dependent on MAPK pathways, since pre-incubation of cells with signaling inhibitors led to more than 85% reduction in cytokine secretion. MAB also triggered a Toll-like receptor 2 (TLR2)-mediated response that led to TNF-alpha production by human monocytes. Accordingly, stimulation of murine TLR2- or myeloid differentiation factor 88-deficient bone marrow-derived macrophages did not elicit TNF-alpha, reinforcing a critical role for TLR2 in MAB-induced cell activation. We concluded that MAB signals human cells through MAPK and TLR2 pathways and triggers more pronounced pro-inflammatory cytokines and chemokines than MAV.
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PMID:Mycobacterium abscessus and M. avium trigger Toll-like receptor 2 and distinct cytokine response in human cells. 1844 Dec 80

The pathophysiology of cystic fibrosis (CF) inflammatory lung disease is not well understood. CF airway epithelial cells respond to inflammatory stimuli with increased production of proinflammatory cytokines as a result of increased NF-kappaB activation. Peroxisome proliferator-activated receptor-gamma (PPARgamma) inhibits NF-kappaB activity and is reported to be reduced in CF. If PPARgamma participates in regulatory dysfunction in the CF lung, perhaps PPARgamma ligands might be useful therapeutically. Cell models of CF airway epithelium were used to evaluate PPARgamma expression and binding to NF-kappaB at basal and under conditions of inflammatory stimulation by Pseudomonas aeruginosa or TNFalpha/IL-1beta. An animal model of CF was used to evaluate the potential of PPARgamma agonists as therapeutic agents in vivo. In vitro, PPARgamma agonists reduced IL-8 and MMP-9 release from airway epithelial cells in response to PAO1 or TNFalpha/IL-1beta stimulation. Less NF-kappaB bound to PPARgamma in CF than normal cells, in two different assays; PPARgamma agonists abrogated this reduction. PPARgamma bound less to its target DNA sequence in CF cells. To test the importance of the reported PPARgamma inactivation by phosphorylation, we observed that inhibitors of ERK, but not JNK, were synergistic with PPARgamma agonists in reducing IL-8 secretion. In vivo, administration of PPARgamma agonists reduced airway inflammation in response to acute infection with P. aeruginosa in CF, but not wild-type, mice. In summary, PPARgamma inhibits the inflammatory response in CF, at least in part by interaction with NF-kappaB in airway epithelial cells. PPARgamma agonists may be therapeutic in CF.
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PMID:Peroxisome proliferator-activated receptor-gamma in cystic fibrosis lung epithelium. 1855 1

We reported earlier that the activation of free-radical-mediated tumor necrosis factor-alpha (TNF-alpha) cascade is the major pathway in the inflammatory lung disease induced by 2-chloroethyl ethyl sulfide (CEES), a mustard gas analog. TNF-alpha induces activating protein 1 (AP-1) activation via phosphorylation of mitogen activated protein kinases (MAPKs). The present study examines the relationship between CEES induced lung injury and MAPKs signaling pathway. Adult guinea pigs received single intratracheal injection of different doses of CEES and were sacrificed at different time points. CEES exposure caused lung injury with evidence of fibrosis. The optimum activation of all members of the MAPKs family (ERK1/2, p38 and JNK1/2) was achieved at 0.5 mg/kg dose and at 1h. No significant change was observed beyond that time point. This led to an activation of AP-1 transcription factors associated with an increase in the protein levels of Fos, activating transcription factor (ATF) and Jun family members. To explore the involvement of AP-1 in cell proliferation, we determined the protein levels of cell cycle protein cyclin D1 and cell differentiation marker proliferating cell nuclear antigen (PCNA). An up regulation of these proteins was observed. Hence it is suggested that CEES exposure causes accumulation of TNF-alpha, which is associated with an activation of MAPK/AP-1 signaling pathway and cell proliferation. Further studies are needed to clarify whether the observed effects are the adaptive responses of the lung or they contribute to the lung injury.
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PMID:Activation of MAPK/AP-1 signaling pathway in lung injury induced by 2-chloroethyl ethyl sulfide, a mustard gas analog. 1867 30

Angiomyolipomas are benign mesenchymal tumours of smooth muscle, blood vessels and fat which occur sporadically or associated with tuberous sclerosis and lymphangioleiomyomatosis (LAM), a rare cystic lung disease. Angiomyolipoma and LAM are caused by loss of function of either the tuberous sclerosis-1 or -2 genes resulting in activation of p70S6kinase (S6K1) and uncontrolled cellular proliferation. LAM and angiomyolipoma can be exacerbated by oestrogens but how this occurs is not understood. To address this question, we created a xenograft tumour system in nude mice using immortalised angiomyolipoma cells. Angiomyolipoma xenografts had active S6K1, p38, p42/44 MAPK and Akt; they grew more rapidly and had greater Akt phosphorylation after oestrogen treatment of tumour-bearing mice. Transcriptional profiling showed oestrogen induced 300 genes including extracellular matrix proteins, proteases, cell cycle regulatory proteins and growth factors including platelet derived growth factor-C (PDGF-C). Biologically active PDGF-C was produced by primary angiomyolipoma cells in culture and PDGF-C protein was present in the neoplastic smooth muscle cells of 5/5 human angiomyolipoma and 4/5 LAM tissues examined by immunohistochemistry. These findings suggest that the response to oestrogen in this model is mediated by activation of Akt and transcriptional events. This model may prove useful for studying the biology and effect of drugs on angiomyolipoma and diseases related to TSC.
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PMID:Analysis of the oestrogen response in an angiomyolipoma derived xenograft model. 1898 5

Idiopathic pulmonary fibrosis is a lethal parenchymal lung disease characterized by denudation of the lung epithelium, fibroblast proliferation, and collagen deposition. Cellular changes underlying disease progression involve injury to alveolar epithelial cells, epithelial to mesenchymal transition, proliferation of alpha-smooth muscle actin (alpha-SMA)-expressing myofibroblasts and of fibroblasts resulting in enhanced deposition of extracellular matrix proteins. Hepatocyte growth factor (HGF) inhibits progression of bleomycin-induced pulmonary fibrosis in mice. The mechanism underlying the inhibitory effect of HGF was investigated in an in vitro model. We show that HGF markedly antagonizes basal and transforming growth factor (TGF)-beta-induced expression of myofibroblast markers such as alpha-SMA, collagen type 1, and fibronectin in rat alveolar epithelial cells. HGF also inhibited TGF-beta-induced alpha-SMA expression in primary murine alveolar epithelial cells. Since TGF-beta is known to regulate alpha-SMA expression, the effect of HGF on components of TGF-beta signaling was investigated. HGF induced expression of Smad7, an inhibitor of TGF-beta signaling, in a mitogen-activated protein kinase-dependent manner. HGF also induced the nuclear export of Smad7 and Smad ubiquitin regulatory factor 1 (Smurf1) to the cytoplasm. HGF-dependent decrease in alpha-SMA was abolished with specific siRNAs targeted to Smad7. Thus, induction of Smad7 by HGF serves to limit acquisition of the myofibroblast phenotype in alveolar epithelial cells.
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PMID:Hepatocyte growth factor inhibits epithelial to myofibroblast transition in lung cells via Smad7. 1898 20


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