Journal
CELLULAR SIGNALLING
Volume 24, Issue 4, Pages 907-913Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2011.12.013
Keywords
Negative feedback effector; Cytokines; MKP-1; p38 MAPK; mRNA stability
Categories
Funding
- Senglet Stiftung (Switzerland)
- University of Sydney
- National Health and Medical Research Council of Australia [570856]
Ask authors/readers for more resources
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 alpha (TNF alpha), we observed that TNF alpha 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 TNF alpha 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 TNFa increases MKP-1 mRNA expression and protein upregulation in a p38 MAPK-dependent manner. INF alpha does not increase MKP-1 transcription (measured by MKP-1 promoter activity); rather, we found that TNF alpha-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 MKP1 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, TNFa concomitantly upregulates the MAPK deactivator MKP-1 to serve as an important negative feedback effector, limiting the extent and duration of pro-inflarnmatory MAPK signaling and cytokine secretion in ASM cells. (C) 2011 Elsevier Inc. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available