 |
|
Extracellular Signal-Related Kinase 1/2 and p38 Mitogen-Activated Protein Kinase Pathways Serve Opposite Roles in Neutrophil Cytotoxicity
Jeffrey L. Johnson, MD;
Ernest E. Moore, MD;
David A. Patrick, MD;
Douglas Y. Tamura, MD;
Garret Zallen, MD;
David J. Elzi;
Christopher C. Silliman, MD, PhD
Arch Surg. 1999;134:1074-1078.
Background Inflammatory stimuli rapidly activate mitogen-activated protein kinases (MAPKs) in neutrophils (PMNs). However, their role in cytotoxic function remains unknown. Elucidating the signals involved in release of cytotoxic agents from PMNs may provide new avenues for therapy in diseases of diminished or excessive PMN function.
Hypothesis The p38 MAPK and extracellular signal-related kinase 1/2 (ERK1/2) modulate superoxide generation and elastase release in activated human PMNs.
Study Design Isolated human PMNs were incubated with specific inhibitors of MAPK pathways, or vehicle control solution, before activation with the bacterial peptide f-Met-Leu-Phe.
Main Outcome Measures The rate of superoxide release from activated PMNs was measured by the superoxide dismutase–inhibitable reduction of cytochrome-c. Elastase release from PMNs was determined by cleavage of the substrate Ala-Ala-Pro-Val-pNA.
Results Superoxide release from activated PMNs was inhibited by blockade of p38 MAPK activation but unaffected by blockade of ERK1/2. Conversely, elastase release was unaffected by p38 MAPK inhibition and increased by ERK1/2 inhibition.
Conclusions Activation of p38 MAPK promotes superoxide release from PMNs activated by f-Met-Leu-Phe. The ERK1/2 pathway may serve as a negative feedback mechanism for granule exocytosis.
From the Departments of Surgery (Drs Johnson, Moore, Tamura, and Zallen and Mr Patrick) and Pediatrics (Mr Elzi and Dr Silliman), Denver Health Medical Center, University of Colorado Health Sciences Center; and the Bonfils Blood Center (Mr Elzi and Dr Silliman), Denver.
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Cholinergic agonists transactivate EGFR and stimulate MAPK to induce goblet cell secretion
Kanno et al.
Am. J. Physiol. Cell Physiol. 2003;284:C988-C998.
ABSTRACT
| FULL TEXT
p38 MAPK inhibition reduces myocardial reperfusion injury via inhibition of endothelial adhesion molecule expression and blockade of PMN accumulation
Gao et al.
Cardiovasc Res 2002;53:414-422.
ABSTRACT
| FULL TEXT
A Novel 14-Kilodalton Protein Interacts with the Mitogen-activated Protein Kinase Scaffold MP1 on a Late Endosomal/Lysosomal Compartment
Wunderlich et al.
J. Cell Biol. 2001;152:765-776.
ABSTRACT
| FULL TEXT
Maximal Human Neutrophil Priming for Superoxide Production and Elastase Release Requires p38 Mitogen-Activated Protein Kinase Activation
Partrick et al.
Arch Surg 2000;135:219-225.
ABSTRACT
| FULL TEXT
|
