L-selectin signaling of neutrophil adhesion and degranulation involves p38 mitogen-activated protein kinase.
The adhesion molecules known as selectins mediate the capture of neutrophils from the bloodstream. We have previously reported that ligation and cross-linking of L-selectin on the neutrophil surface enhances the adhesive function of beta(2)-integrins in a synergistic manner with chemotactic agonists. In this work, we examined degranulation and adhesion of neutrophils in response to cross-linking of L-selectin and addition of interleukin-8. Cross-linking of L-selectin induced priming of degranulation that was similar to that observed with the alkaloid cytochalasin B. Activation mediated by L-selectin of neutrophil shape change and adhesion through CD11b/CD18 were strongly blocked by Merck C, an imidazole-based inhibitor of p38 mitogen-activated protein kinase (MAPK), but not by a structurally similar non-binding regioisomer. Priming by L-selectin of the release of secondary, tertiary, and secretory, but not primary, granules was blocked by inhibition of p38 MAPK. Peak phosphorylation of p38 MAPK was observed within 1 min of cross-linking L-selectin, whereas phosphorylation of ERK1/2 was highest at 10 min. Phosphorylation of p38 MAPK, but not ERK1/2, was inhibited by Merck C. These data suggest that signal transduction as a result of clustering L-selectin utilizes p38 MAPK to effect neutrophil shape change, integrin activation, and the release of secondary, tertiary, and secretory granules.
Smolen
J E
JE
Department of Pediatrics, Leukocyte Biology Section, Baylor College of Medicine, Houston, Texas 77030-2600, USA. jsmolen@bcm.tmc.edu
Petersen
T K
TK
Koch
C
C
O'Keefe
S J
SJ
Hanlon
W A
WA
Seo
S
S
Pearson
D
D
Fossett
M C
MC
Simon
S I
SI
D002448:Cell Adhesion / Q000187:drug effects; D048429:Cell Size; D003432:Cross-Linking Reagents / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007700:Kinetics; D019041:L-Selectin / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018375:Neutrophil Activation; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases
D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D016177:Macrophage-1 Antigen; D019041:L-Selectin; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases