MKP-1: a negative feedback effector that represses MAPK-mediated pro-inflammatory signaling pathways and cytokine secretion in human airway smooth muscle cells.
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.
Respiratory Research Group, Faculty of Pharmacy, University of Sydney, NSW 2006, Australia.
Melanie
M
Manetsch
Wenchi
W
Che
Petra
P
Seidel
Yang
Y
Chen
Alaina J
AJ
Ammit
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D004852:Epoxy Compounds / Q000494:pharmacology; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D010616:Phenanthrenes / Q000494:pharmacology; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000494:pharmacology; D020871:RNA Stability / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004224:Diterpenes; D004852:Epoxy Compounds; D006657:Histones; D007093:Imidazoles; D016209:Interleukin-8; D010616:Phenanthrenes; D011725:Pyridines; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C001899:triptolide; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C093642:SB 203580