Mitogen‐activated protein kinases and asthma

Pelaia, Girolamo; Cuda, Giovanni; Vatrella, Alessandro; Gallelli, Luca; Caraglia, Michele; Marra, Monica; Abbruzzese, Alberto; Caputi, M; Maselli, Roberta; Costanzo, Francesco; Sa, Marsico

doi:10.1002/jcp.20169

Cited by 100 publications

(72 citation statements)

References 134 publications

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“…These findings were confirmed by stimulating the cells with nucleotides in the presence of SB-203580, a specific p38 MAPK inhibitor. It is known that p38 MAPK can phosphorylate numerous downstream substrates, including heat shock protein (HSP27), transcription factors ATF2/6, Chop, Max, MEF2C, nuclear histone H3, or other kinases, such as PRAK (p38-regulated/activated protein kinase), MNK1/2 (MAPK-interacting kinase 1/2), MSK1 (mitogen-and stressactivated kinase 1), and MAPK-activated protein kinase 2 (MAPKAP-K2) (51). It has also been reported that p38 MAPK-dependent synthesis of cytokines, including IL-6, involves MAPKAP-K2.…”

Section: Discussionmentioning

confidence: 99%

Nucleotides induce IL-6 release from human airway epithelia via P2Y₂and p38 MAPK-dependent pathways

Douillet

Robinson²,

Milano³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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Extracellular nucleotides can mediate a variety of cellular functions via interactions with purinergic receptors. We previously showed that mechanical ventilation (MV) induces airway IL-6 and ATP release, modifies luminal nucleotide composition, and alters lung purinoceptor expression. Here we hypothesize that extracellular nucleotides induce secretion of IL-6 by small airway epithelial cells (SAEC). Human SAEC were stimulated with nucleotides in the presence or absence of inhibitors. Supernatants were analyzed for IL-6 and lysates for p38 MAPK activity by ELISA. RNA was analyzed by real-time RT-PCR. Rats (n ϭ 51) were randomized to groups as follows: control, small-volume MV, largevolume MV, large-volume MV-intratracheal apyrase, or small-volume MV-intratracheal adenosine 5Ј-O-(3-thiotriphosphate) (ATP␥S). After 1 h of MV, bronchoalveolar lavage fluid was analyzed for ATP and IL-6 by luminometry and ELISA. ATP and ATP␥S increased SAEC IL-6 secretion in a time-and dose-dependent manner, an effect inhibited by apyrase. Agonists were ranked in the following order: ATP␥S Ͼ ATP ϭ UTP Ͼ ADP ϭ adenosine Ͼ 2-methylthio-ADP ϭ control. SB-203580, but not U-0126 or JNK1 inhibitor, decreased nucleotide effects. Additionally, nucleotides induced p38 MAPK phosphorylation. Inhibitors of Ca 2ϩ signaling, phospholipase C, transcription, and translation decreased IL-6 release. Furthermore, nucleotides increased IL-6 expression. In vivo, large-volume MV increased airway ATP and IL-6 concentrations. IL-6 release was decreased by apyrase and increased by ATP␥S. Extracellular nucleotides induce P2Y2-mediated secretion of IL-6 by SAEC via Ca 2ϩ , phospholipase C, and p38 MAPK-dependent pathways. This effect is dependent on transcription and translation. Our findings were confirmed in an in vivo model, thus demonstrating a novel mechanism of nucleotideinduced IL-6 secretion by airway epithelia. cytokine; inflammation; purine; purinergic; ventilator-associated lung injury; interleukin-6; mitogen-activated protein kinase

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Section: Discussionmentioning

confidence: 99%

Nucleotides induce IL-6 release from human airway epithelia via P2Y₂and p38 MAPK-dependent pathways

Douillet

Robinson²,

Milano³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…1d). Since this pathway is undoubtedly activated in asthma and chronic obstructive pulmonary disease and may contribute to the inflammation and even remodelling of the airway wall [168], it is tempting to speculate that further activation of ERK-dependent signalling may account for some of the adverse clinical observations made with b 2 -adrenoceptor agonists described above [169,170]. Such effects, as are often the case, require appropriate validation in primary cells relevant to the airways or suitable animal models.…”

Section: Promiscuous G-protein Couplingmentioning

confidence: 99%

Beyond the dogma: novel β₂-adrenoceptor signalling in the airways

Giembycz

Newton²

2006

Eur Respir J

132

118

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b 2 -Adrenoceptor agonists evoke rapid bronchodilatation and are the mainstay of the treatment of asthma symptoms worldwide. The mechanism of action of this class of compounds is believed to involve the stimulation of adenylyl cyclase and subsequent activation of the cyclic adenosine monosphosphate (cAMP)/cAMP-dependent protein kinase cascade.This classical model of b 2 -adrenoceptor-mediated signal transduction is deeply entrenched, but there is compelling evidence that agonism of b 2 -adrenoceptors can lead to the activation of multiple effector pathways, which now compels researchers in academia and the pharmaceutical industry alike to think beyond the traditional dogma. Therefore, the regulation by b 2 -adrenoceptor agonists of responses, including airways smooth muscle tone and the secretory capacity of the epithelium and pro-inflammatory/immune cells, may be highly complex, involving both cAMPdependent and -independent mechanisms that, in many cases, may act in concert.In this article, the current status of b 2 -adrenoceptor-mediated signalling in the airways is reviewed in the context of understanding mechanisms that may underlie both the beneficial and detrimental effects of these drugs in asthma symptom management.

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“…These pro-inflammatory cytokines and chemokines, together with IL-1b, strongly activate the p38 subgroup of mitogen-activated protein kinases (MAPKs), a family of signal transduction enzymes that also include extracellular signal-regulated kinases (ERK) and c-jun NH 2 -terminal kinases (JNK) [4]. MAPKs are organised hierarchically into three modules, operating via a phosphorylation cascade that converts them into activated forms, thereby enabling their interaction with cytoplasmic substrates and translocation to the nucleus, where many MAPK targets, such as transcription factors and histones, are located [5]. The ERK pathway is stimulated in particular by G-protein coupled receptors and growth factors involved in cell proliferation, differentiation and survival, whereas JNK and p38 modules are activated mainly by cytokines implicated in inflammation and apoptosis [6].…”

mentioning

confidence: 99%

Increased activation of p38 MAPK in COPD

Renda¹,

Baraldo²,

Pelaia³

et al. 2007

Eur Respir J

235

157

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Inflammation, oxidative stress and apoptosis, which are involved in chronic obstructive pulmonary disease (COPD) pathogenesis, may activate the p38 subgroup of mitogenactivated protein kinases (MAPKs). Therefore, the aim of the present study was to evaluate the expression of the phosphorylated, active form of p38 MAPK (phospho-p38) in the lungs of COPD patients.Surgical specimens were obtained from 18 smokers with COPD at different stages of disease severity, plus nine smoking and eight nonsmoking subjects with normal lung function. Phosphop38+ cells were quantified by immunohistochemistry in both alveolar spaces and alveolar walls. Moreover, a Western blot analysis of phospho-p38 and total p38a isoform expressed by alveolar macrophages was performed.Phospho-p38+ alveolar macrophages and phospho-p38+ cells in alveolar walls were increased in patients with severe and mild/moderate COPD, compared with smoking and nonsmoking controls. Moreover, they were inversely correlated to values of forced expiratory volume in one second (FEV1) and FEV1/forced vital capacity. Western blot analysis showed that phosphorylated p38, but not the total p38a isoform, was specifically increased in alveolar macrophages from COPD patients.Activation of the p38 mitogen-activated protein kinase pathway appears to be involved in the pathogenesis of chronic obstructive pulmonary disease. The present findings suggest that this protein may be a suitable pharmacological target for therapeutic intervention.

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Mitogen‐activated protein kinases and asthma

Cited by 100 publications

References 134 publications

Nucleotides induce IL-6 release from human airway epithelia via P2Y₂and p38 MAPK-dependent pathways

Nucleotides induce IL-6 release from human airway epithelia via P2Y₂and p38 MAPK-dependent pathways

Beyond the dogma: novel β₂-adrenoceptor signalling in the airways

Increased activation of p38 MAPK in COPD

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Mitogen‐activated protein kinases and asthma

Cited by 100 publications

References 134 publications

Nucleotides induce IL-6 release from human airway epithelia via P2Y2and p38 MAPK-dependent pathways

Nucleotides induce IL-6 release from human airway epithelia via P2Y2and p38 MAPK-dependent pathways

Beyond the dogma: novel β2-adrenoceptor signalling in the airways

Increased activation of p38 MAPK in COPD

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Product

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Nucleotides induce IL-6 release from human airway epithelia via P2Y₂and p38 MAPK-dependent pathways

Nucleotides induce IL-6 release from human airway epithelia via P2Y₂and p38 MAPK-dependent pathways

Beyond the dogma: novel β₂-adrenoceptor signalling in the airways