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)

Asthma is characterized by an irreversible subepithelial fibrosis with the appearance of myofibroblasts, which can be now considered important early participants in inflammatory responses as well as potential targets for anti-inflammatory drugs. In this study, we show that fluticasone propionate (FP), a powerful inhaled corticosteroid (ICS), displays novel anti-inflammatory effects on human lung fibroblasts during their myofibroblastic differentiation. Indeed, FP inhibits in lung myofibroblasts, at a very early stage of differentiation, the activation of Janus kinase/STAT pathways induced by IL-13 (tyrosine kinase 2, STAT1, STAT3, STAT6, mitogen-activated protein kinase). Contrarily, in mildly or fully differentiated myofibroblastic cultures, FP still displays a potential anti-inflammatory activity even if it only inhibits tyrosine kinase 2 phosphorylation. Moreover, FP inhibits constitutive and TGF-beta-induced expression of alpha-smooth muscle actin, the main marker of myofibroblastic differentiation, both in very early and in mild differentiated myofibroblasts. Finally, FP displays an additional powerful anti-inflammatory effect, decreasing nuclear translocation of NF-kappaB independent of the degree of myofibroblastic differentiation. These data 1) suggest that myofibroblasts are priority targets for ICS, which is able to revert them to a normal phenotype even if they appear to be already engaged in their differentiation, and 2) may help to explain why asthma is improved by an early ICS treatment, whereas advanced asthma is more resistant to these drugs.
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PMID:Novel anti-inflammatory effects of the inhaled corticosteroid fluticasone propionate during lung myofibroblastic differentiation. 1167 49

IL-4 and IL-13 are related cytokines which induce both pro- and anti-inflammatory effects depending on the cell type they act upon and the nature of the receptors expressed. The type I receptor complex is composed of the IL-4Ralpha and gammac and only binds IL-4, whereas, in the type II receptor, IL-4Ralpha dimerizes with IL-13Ralpha1 upon either IL-4 or IL-13 binding. Another ligand binding chain potentially implicated in the IL-4/IL-13 receptor has been described, the IL-13Ralpha2, but the regulation of its expression and its role in IL-4/IL-13 transduction is poorly understood. In this study we report that IL-4 and IL-13 upregulate IL-13Ralpha2 at both the mRNA and protein levels in the keratinocyte cell line HaCaT. In these cells, IL-4 or IL-13 were shown to activate the Janus Kinases JAK1 and JAK2, the transcription factor STAT6, and the ERK and p38 mitogen-activated protein kinases. We show that IL-4 or IL-13-induced IL-13Ralpha2 mRNA expression was inhibited by the ERK inhibitor U0126, the JAK inhibitor AG490 and, to a lesser extent, the p38 MAPK inhibitor SB203580. Moreover, expression of a constitutive active mutant of STAT6 alone did not modify IL-13Ralpha2 mRNA expression, but potentiated the effects of IL-4 or IL-13 on IL-13Ralpha2 expression. The constitutive active mutants of MEK1 or MKK6 increased the level of expression of IL-13Ralpha2 mRNA even in absence of stimulation. Our findings demonstrate, for the first time, that IL-4 and IL-13 can induce IL-13Ralpha2 expression in keratinocytes, and that the ERK and p38 MAPK together with JAK2 and STAT6 play a critical role in this process.
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PMID:Induction of the IL-13 receptor alpha2-chain by IL-4 and IL-13 in human keratinocytes: involvement of STAT6, ERK and p38 MAPK pathways. 1170

Human airway smooth muscle (HASM) cells express interleukin (IL)-13 and IL-4 receptors and respond to these cytokines with signal transducer and activator of transcription-6 and extracellular signal-regulated kinase (ERK) activation. The purpose of this study was to determine whether IL-13 and/or IL-4 influence eotaxin release in HASM cells and whether the ERK mitogen-activated protein (MAP) kinase pathway is involved in these events. Eotaxin release into HASM cell supernatants was assayed by ELISA, and eotaxin mRNA expression was determined by Northern blot analysis. Pretreatment with either IL-13 or IL-4 resulted in a concentration- and time-dependent release of eotaxin, although IL-4 was more effective. Eotaxin release was approximately twice baseline after treatment with 50 ng/ml IL-13 or IL-4 (P < 0.001). IL-13 and IL-4 also acted synergistically with tumor necrosis factor (TNF)-alpha to induce eotaxin release: TNF-alpha alone (10 ng/ml for 24 h) resulted in an approximately fourfold increase in eotaxin release, whereas TNF-alpha in combination with IL-13 or IL-4 resulted in 10- or 20-fold increases (P < 0.05). Similar results were obtained for eotaxin mRNA expression. Pretreatment with either U-0126 (10 microM) or PD-98059 (30 microM), both inhibitors of MAP/ERK kinase, the enzyme upstream of ERK, inhibited IL-13- or IL-4-induced eotaxin release (P < 0.05). U-0126 also inhibited IL-13, and TNF-alpha induced mRNA expression. Our results indicate that IL-13 and IL-4 cause eotaxin release in HASM cells through a mechanism that, in part, involves ERK activation and suggest that the smooth muscle may be an important source of chemokines leading to eosinophil recruitment in asthma.
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PMID:IL-13 and IL-4 cause eotaxin release in human airway smooth muscle cells: a role for ERK. 1188 Mar 12

The biologic activities of interleukin (IL)-13 and IL-4 often overlap, and evidence supports their importance in atopic disease and airways hyperresponsiveness. Here, their capacity to release eosinophil-activating cytokines was examined in cultured human airway smooth muscle. IL-13 and IL-4 induced selective release of eotaxin with no effect on granulocyte-macrophage colony-stimulating factor, regulated upon activation, normal T-cell expressed and secreted (RANTES), or IL-8. A profound synergistic increase in eotaxin release occurred when IL-13 or IL-4 was combined with IL-1beta that was abrogated by a neutralizing antibody to the IL-4 receptor alpha (IL-4Ralpha)-chain but not to the IL-2 receptor gamma (IL-2Rgamma)-chain. Expression of cell surface IL-4 receptors and IL-4Ralpha in lysates was constitutive and unchanged by treatment with IL-13 or IL-4 alone or in combination with IL-1beta. Activation of IL-4Ralpha by IL-13 or IL-4 induced signal transducer and activation of transcription-6 (STAT6), p42/ p44 ERK, p38, and to a lesser extent, SAPK/JNK mitogen-activated protein kinase phosphorylation. STAT6 and MAP kinase activation by IL-13 or IL-4 was not further potentiated after combined stimulation with IL-1beta. However, eotaxin release induced by IL-13 or IL-4 alone, and in combination with IL-1beta, was prevented by the MEK inhibitor U 0126 and by the p38 inhibitor SB 202190. Collectively, the data suggest that selective eotaxin release induced either by IL-13 and IL-4 or when combined with IL-1beta is mediated by a constitutive cell surface IL-4Ralpha and the activation of multiple intracellular pathways.
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PMID:Selective induction of eotaxin release by interleukin-13 or interleukin-4 in human airway smooth muscle cells is synergistic with interleukin-1beta and is mediated by the interleukin-4 receptor alpha-chain. 1195 62

1. IL-13 is an important mediator in inflammatory diseases such as asthma. IL-13 is mainly produced by T cells. However, signalling pathways leading to induction of this cytokine are not well-characterized. We analysed the regulation of IL-13 in human peripheral blood mononuclear cells and CD4(+) T cells. 2. Cyclosporine (CsA) and FK-506 inhibited IL-13 synthesis, when cells were stimulated by TPA/ionomycin. However, stimulation by alpha-CD3/alpha-CD28 led to an enhanced IL-13 synthesis. 3. NF-kappa B inhibitor N-tosyl-L-lysine chloromethylketone (TLCK) inhibited IL-13 synthesis more effectively after TPA/ionomycin stimulation. After alpha-CD3/alpha-CD28 stimulation, only 300 microM TLCK inhibited IL-13 synthesis. Dexamethasone inhibited IL-13 equally effective after alpha-CD3/alpha-CD28 and TPA/ionomycin stimulation. 4. p38 MAPK inhibitor SB203580 inhibited IL-13 synthesis only partially. MEK inhibitor U0126 inhibited TPA/ionomycin induced IL-13 synthesis very effectively, whereas alpha-CD3/alpha-CD28 stimulated IL-13 induction was resistant to this drug. 5. These results were confirmed in purified CD4(+) T cells. In difference to PBMCs alpha-CD3/alpha-CD28 stimulated IL-13 synthesis was effectively inhibited by CsA, FK-506 and U0126. 6. Therefore U0126 was tested in an animal model of allergic asthma. We could demonstrate for the first time that inhibition of the MEK - ERK cascade is a therapeutic option for asthma. Intraperitoneal administration of 10 mg kg(-1) U0126 reduced lung eosinophilia in ovalbumin-challenged Brown Norway rats by 44%. 7. These results demonstrate that different signalling pathways are involved in regulating IL-13 synthesis in primary human T cells. Characterizing highly potent inhibitors of IL-13 synthesis can be exploited to identify new drugs to treat immunological diseases such as asthma.
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PMID:Regulation of IL-13 synthesis in human lymphocytes: implications for asthma therapy. 1195 94

Although human basophils modulate allergic diseases by secreting histamine, leukotriene C(4), interleukin (IL)-4, and IL-13, the intermediary signals controlling the release of these mediators are poorly understood. Here, we show that p38 mitogen-activated protein kinase (MAPK) crucially affects basophil activation following stimulation with various secretagogues. Phosphorylation of p38 MAPK occurred within 5 min following anti-immunoglobulin (Ig)E stimulation, but was more rapidly activated in basophils stimulated with formyl-Met-Leu-Phe or A23187. Additionally, activation of p38 MAPK to the above stimuli was dependent on extracellular influx and intracellular mobilization of calcium. SB 203580, a specific p38 MAPK inhibitor, blocked anti-IgE-induced secretion of all basophil mediators and reduced not only p38 MAPK, but also extracellular signal-regulated kinases 1 and 2 activity, whereas the MAPK antagonist, PD 098059, did not affect p38 MAPK. IgE-dependent activation of p38 MAPK and MKK3/6 was affected by LY 294002 and wortmannin, suggesting that these kinases are targets for phosphatidylinositol 3 kinase (PI 3-K). We conclude that p38 MAPK is a pivotal regulator of basophil function downstream of PI 3-K activation and calcium mobilization.
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PMID:Regulation of mediator secretion in human basophils by p38 mitogen-activated protein kinase: phosphorylation is sensitive to the effects of phosphatidylinositol 3-kinase inhibitors and calcium mobilization. 1214 31

Initiation of T lymphocyte responses to most Ags requires concurrent stimulation through the TCR and costimulatory receptors such as CD28. Following initial activation, secondary receptors are up-regulated that can costimulate T cells in concert with TCR engagement. One such receptor is the TNFR family member CD30. In this study, we report that unlike CD28, ligation of CD30 on normal effector T cells induces IL-13 production in the absence of concurrent TCR engagement. TCR-independent CD30-mediated IL-13 release correlated with activation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase (MAPK), and NF-kappaB, and was completely inhibited by the expression of a TNFR-associated factor 2 (TRAF2) dominant-negative transgene (TRAF2.DN-Tg), but not by that of an I-kappaBalpha dominant-negative transgene. In parallel, expression of the TRAF2.DN-Tg selectively prevented the induction of c-Jun N-terminal kinase and p38 MAPK, but not that of NF-kappaB. Furthermore, IL-13 production was reduced in a dose-dependent manner by the p38 MAPK inhibitor SB203580. Together, these results suggest that TCR-independent CD30-mediated production of IL-13 is triggered by association of CD30 with TRAF family members and subsequent activation of p38 MAPK. Inasmuch as IL-13 can promote airway inflammation and cancer progression, production of IL-13 in a TCR-independent manner has important pathological implications in vivo.
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PMID:TCR-independent CD30 signaling selectively induces IL-13 production via a TNF receptor-associated factor/p38 mitogen-activated protein kinase-dependent mechanism. 1219 14

Mast cells secrete multiple cytokines and play an important role in allergic inflammation. Although it is widely accepted that bacteria infection occasionally worsens allergic airway inflammation, the mechanism has not been defined. In this study, we show that LPS induced Th2-associated cytokine production such as IL-5, IL-10, and IL-13 from mast cells and also synergistically enhanced production of these cytokines induced by IgE cross-linking. LPS-mediated Th2-type cytokine production was abolished in mouse bone marrow-derived mast cells derived from C3H/HeJ mice, suggesting that Toll-like receptor 4 is essential for the cytokine production. Furthermore, we found that mitogen-activated protein kinases including extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 kinase were activated by LPS stimulation in bone marrow-derived mast cells. Inhibition of extracellular signal-regulated kinase activation has little effect on LPS-mediated cytokine production. In contrast, inhibition of c-Jun N-terminal kinase activation significantly suppressed both IL-10 and IL-13 expression at both mRNA and protein levels. Interestingly, although inhibition of p38 did not down-regulate the mRNA induction, it moderately decreased all three cytokine productions by LPS. These results indicate that LPS-mediated production of IL-5, IL-10, and IL-13 was distinctly regulated by mitogen-activated protein kinases. Our findings may indicate a clue to understanding the mechanisms of how bacteria infection worsens the clinical features of asthma.
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PMID:Th2 cytokine production from mast cells is directly induced by lipopolysaccharide and distinctly regulated by c-Jun N-terminal kinase and p38 pathways. 1224 75

Decreased responsiveness to beta-adrenergic receptor agonists is a characteristic feature of human asthma. One explanation for this observation is that cytokines released in the asthmatic airway have direct effects on airway smooth muscle cells that reduce the ability of the cells to relax in response to beta-agonists. This review summarizes data indicating that both inflammatory cytokines, such as IL-1beta and TNF-alpha, and Th2 cytokines, such as IL-13 and IL-5, have the capacity to decrease the ability of cultured airway smooth muscle cells to relax or to generate cyclic AMP in response to beta-agonists, such as isoproterenol. These effects are observed in smooth muscle from human airways and airway smooth muscle of other species. In human airway smooth muscle, the effects of IL-1beta and TNF-alpha appear to be mediated through expression of cyclooxygenase-2, whereas the effect of IL-13 requires activation of the extracellular signal-regulated kinase-mitogen-activated protein kinase pathway. IL-1beta and TNF-alpha also inhibit the ability of beta-agonists to drive airway smooth muscle gene expression through pathways dependent on cyclic AMP response elements. Understanding the mechanistic basis for the effects of these cytokines may prove to be an important step in improving the efficacy of beta-agonists for the treatment of asthma.
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PMID:Cytokine regulation of beta-adrenergic responses in airway smooth muscle. 1246 33

Synthetic function of airway smooth muscle (ASM), defined as secretion of cytokines or chemokines, may regulate airway inflammatory responses in chronic obstructive lung diseases. Because bradykinin (BK) and interleukin (IL)-6 may play important roles in the regulation of airway inflammation, we tested whether BK induces IL-6 expression from human ASM cells. BK stimulates IL-6 release in a concentration-dependent (0.001-10 micro M) and time-dependent (2-24 h) manner. The increases in IL-6 protein and total mRNA were inhibited by the selective B(2) receptor antagonist HOE-140 but not by the selective B(1) receptor antagonist desArg(9)(Leu(8))-BK. Actinomycin D (a transcription inhibitor), dexamethasone, indomethacin, IL-4, and IL-13 (Th(2) type cytokines) inhibited the expression of IL-6 by BK. In contrast, BK-induced IL-6 secretion was enhanced by exogenous prostaglandin E(2) and salmeterol. Using immunoblot analysis, we showed that BK activates ERK1/2 and p38 mitogen-activated protein kinases (MAPK). Blocking ERK1/2 with PD98059 or p38 MAPK with SB203580 reduced BK-induced IL-6 expression. BK also activates luciferase activity in ASM cells transfected with a reporter plasmid containing AP-1 enhancer elements. BK-induced, AP-1-dependent transcription was inhibited by indomethacin and dexamethasone. Curcumin, an inhibitor of AP-1, also reduced BK-induced IL-6 expression. These data show that BK, via the B(2) receptor, induces IL-6 expression in ASM cells by involving ERK1/2 and p38 MAPK signaling pathways and the AP-1 transcription factor. Moreover, IL-6 secretion by BK is sensitive to corticosteroids and is regulated by Th(2)-derived cytokines.
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PMID:Bradykinin induces interleukin-6 production in human airway smooth muscle cells: modulation by Th2 cytokines and dexamethasone. 1259 59


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