MKP-1: A negative feedback effector that represses MAPK-mediated pro-inflammatory signaling pathways and cytokine secretion in human airway smooth muscle cells

Manetsch, M; Che, W; Seidel, P; Chen, Y; Ammit, AJ

MKP-1: A negative feedback effector that represses MAPK-mediated pro-inflammatory signaling pathways and cytokine secretion in human airway smooth muscle cells

Manetsch, M Che, W Seidel, P Chen, Y Ammit, AJ

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Publication Type:: Journal Article
Citation:: Cellular Signalling, 2012, 24 (4), pp. 907 - 913
Issue Date:: 2012-04-01

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Field	Value	Language
dc.contributor.author	Manetsch, M	en_US
dc.contributor.author	Che, W	en_US
dc.contributor.author	Seidel, P	en_US
dc.contributor.author	Chen, Y	en_US
dc.contributor.author	Ammit, AJ https://orcid.org/0000-0003-0555-2544	en_US
dc.date.available	2011-12-12	en_US
dc.date.issued	2012-04-01	en_US
dc.identifier.citation	Cellular Signalling, 2012, 24 (4), pp. 907 - 913	en_US
dc.identifier.issn	0898-6568	en_US
dc.identifier.uri	http://hdl.handle.net/10453/114884
dc.description.abstract	Airway smooth muscle (ASM) plays an important immunomodulatory role in airway inflammation in asthma. In our previous in vitro studies in ASM cells delineating the pro-inflammatory mitogen-activated protein kinase (MAPK) signaling pathways activated by tumor necrosis factor α (TNFα), we observed that TNFα concomitantly induces the rapid, but transient, upregulation of the anti-inflammatory protein-mitogen-activated protein kinase phosphatase 1 (MKP-1). As this was suggestive of a negative feedback loop, the aim of this study was to investigate the molecular mechanisms of MKP-1 upregulation by TNFα and to determine whether MKP-1 is a negative feedback effector that represses MAPK-mediated pro-inflammatory signaling pathways and cytokine secretion in ASM cells. Herein, we show that TNFα increases MKP-1 mRNA expression and protein upregulation in a p38 MAPK-dependent manner. TNFα does not increase MKP-1 transcription (measured by MKP-1 promoter activity); rather, we found that TNFα-induced MKP-1 mRNA stability is regulated by the p38 MAPK pathway. Inhibiting MKP-1 upregulation (with triptolide) demonstrated the precise temporal control exerted on MAPK signaling by MKP-1. In the absence of MKP-1, downstream phosphoprotein targets of MAPKs (such as MSK-1 and histone H3) are not turned off at the right time, allowing pro-inflammatory pathways to continue in an unrestrained manner. This is confirmed by knocking-down MKP-1 by siRNA where enhanced secretion of the neutrophil chemoattractant cytokine-interleukin 8 was detected in the absence of MKP-1. Thus, by activating p38 MAP kinase, TNFα concomitantly upregulates the MAPK deactivator MKP-1 to serve as an important negative feedback effector, limiting the extent and duration of pro-inflammatory MAPK signaling and cytokine secretion in ASM cells. © 2011 Elsevier Inc.	en_US
dc.relation.ispartof	Cellular Signalling	en_US
dc.relation.isbasedon	10.1016/j.cellsig.2011.12.013	en_US
dc.subject.classification	Biochemistry & Molecular Biology	en_US
dc.subject.mesh	Bronchi	en_US
dc.subject.mesh	Myocytes, Smooth Muscle	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Inflammation	en_US
dc.subject.mesh	Epoxy Compounds	en_US
dc.subject.mesh	Diterpenes	en_US
dc.subject.mesh	Imidazoles	en_US
dc.subject.mesh	Pyridines	en_US
dc.subject.mesh	Phenanthrenes	en_US
dc.subject.mesh	p38 Mitogen-Activated Protein Kinases	en_US
dc.subject.mesh	Ribosomal Protein S6 Kinases, 90-kDa	en_US
dc.subject.mesh	Tumor Necrosis Factor-alpha	en_US
dc.subject.mesh	Histones	en_US
dc.subject.mesh	RNA, Small Interfering	en_US
dc.subject.mesh	Anti-Inflammatory Agents, Non-Steroidal	en_US
dc.subject.mesh	Interleukin-8	en_US
dc.subject.mesh	Signal Transduction	en_US
dc.subject.mesh	Gene Expression Regulation	en_US
dc.subject.mesh	RNA Stability	en_US
dc.subject.mesh	Dual Specificity Phosphatase 1	en_US
dc.subject.mesh	Promoter Regions, Genetic	en_US
dc.subject.mesh	Feedback, Physiological	en_US
dc.subject.mesh	Primary Cell Culture	en_US
dc.title	MKP-1: A negative feedback effector that represses MAPK-mediated pro-inflammatory signaling pathways and cytokine secretion in human airway smooth muscle cells	en_US
dc.type	Journal Article
utslib.citation.volume	4	en_US
utslib.citation.volume	24	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	1116 Medical Physiology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access
pubs.issue	4	en_US
pubs.publication-status	Published	en_US
pubs.volume	24	en_US

Abstract:

Airway smooth muscle (ASM) plays an important immunomodulatory role in airway inflammation in asthma. In our previous in vitro studies in ASM cells delineating the pro-inflammatory mitogen-activated protein kinase (MAPK) signaling pathways activated by tumor necrosis factor α (TNFα), we observed that TNFα concomitantly induces the rapid, but transient, upregulation of the anti-inflammatory protein-mitogen-activated protein kinase phosphatase 1 (MKP-1). As this was suggestive of a negative feedback loop, the aim of this study was to investigate the molecular mechanisms of MKP-1 upregulation by TNFα and to determine whether MKP-1 is a negative feedback effector that represses MAPK-mediated pro-inflammatory signaling pathways and cytokine secretion in ASM cells. Herein, we show that TNFα increases MKP-1 mRNA expression and protein upregulation in a p38 MAPK-dependent manner. TNFα does not increase MKP-1 transcription (measured by MKP-1 promoter activity); rather, we found that TNFα-induced MKP-1 mRNA stability is regulated by the p38 MAPK pathway. Inhibiting MKP-1 upregulation (with triptolide) demonstrated the precise temporal control exerted on MAPK signaling by MKP-1. In the absence of MKP-1, downstream phosphoprotein targets of MAPKs (such as MSK-1 and histone H3) are not turned off at the right time, allowing pro-inflammatory pathways to continue in an unrestrained manner. This is confirmed by knocking-down MKP-1 by siRNA where enhanced secretion of the neutrophil chemoattractant cytokine-interleukin 8 was detected in the absence of MKP-1. Thus, by activating p38 MAP kinase, TNFα concomitantly upregulates the MAPK deactivator MKP-1 to serve as an important negative feedback effector, limiting the extent and duration of pro-inflammatory MAPK signaling and cytokine secretion in ASM cells. © 2011 Elsevier Inc.

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http://hdl.handle.net/10453/114884