Extracellular signal-related kinase 1/2 and p38 mitogen-activated protein kinase pathways serve opposite roles in neutrophil cytotoxicity.
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.


OBJECTIVE
The p38 MAPK and extracellular signal-related kinase 1/2 (ERK1/2) modulate superoxide generation and elastase release in activated human PMNs.


METHODS
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.


METHODS
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.
Johnson
J L
JL
Department of Surgery, University of Colorado Health Sciences Center, Denver 80204, USA.
Moore
E E
EE
Partrick
D A
DA
Tamura
D Y
DY
Zallen
G
G
Elzi
D J
DJ
Silliman
C C
CC
Patrick
D A
DA
D003602:Cytotoxicity, Immunologic; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009504:Neutrophils / Q000276:immunology*; D010196:Pancreatic Elastase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D013481:Superoxides; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010196:Pancreatic Elastase