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J. Biol. Chem., Vol. 276, Issue 24, 21039-21045, June 15, 2001
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From the Cellular adhesion molecules such as
E-selectin function to recruit leukocytes into the inflammatory lesions
of diseases such as rheumatoid arthritis (RA) and atherosclerosis.
Monocytes are the key components of the cellular infiltrates present in
these disorders. We hypothesized that soluble E-selectin (sE-selectin) might mediate the chemotaxis of monocytes. In this report, we show that
sE-selectin induced normal human peripheral blood monocyte migration in the nanomolar range in a
concentration-dependent manner. Neutralization studies
using RA human joint synovial fluids and anti-E-selectin antibody
showed a mean 31% reduction in RA synovial fluid-mediated monocyte
chemotaxis (p < 0.05), indicating that sE-selectin is
a major monocyte recruiter in RA. Next, we investigated the role of
tyrosine phosphorylation pathways in sE-selectin-induced monocyte
chemotaxis. Human peripheral blood monocytes stimulated with
sE-selectin showed a time-dependent increase in the
tyrosine phosphorylation of a broad range of cellular proteins,
predominantly in the molecular size range of Src family kinases
(50-60 kDa) and mitogen-activated protein kinases (MAPKs). Western
blot analysis of Src family kinases showed a time-dependent increase in Src, Hck, and Lyn phosphorylation. The pretreatment of
monocytes with the Src inhibitor AG1879:
4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolol[3,4-d]pyrimidine (PP2) prior to stimulation with sE-selectin markedly inhibited Hck and Lyn phosphorylation, whereas the phosphorylation of Src was
partially inhibited. In addition, the sE-selectin stimulation of
monocytes resulted in the increased phosphorylation of extracellular signal-related kinase (ERK1/2) and p38 MAPK. The pretreatment of
monocytes with PP2 showed 89 and 83% inhibition of ERK1/2 and p38 MAPK
phosphorylation, respectively. sE-selectin also showed a
time-dependent activation of Ras kinase. Furthermore, the
pretreatment of monocytes with PP2 completely inhibited
sE-selectin-mediated monocyte chemotaxis. Taken together, our data
demonstrate a novel function for sE-selectin as a monocyte chemotactic
agent and suggest that sE-selectin might be mediating its biological
functions through the Src-MAPK pathway.
Soluble E-selectin Induces Monocyte Chemotaxis through Src Family
Tyrosine Kinases*
,, and§¶
Department of Medicine, Northwestern
University Medical School, Chicago, Illinois 60611 and the
§ Veterans Affairs, Lakeside Division, Chicago Health
Care System, Chicago, Illinois 60611
*
This work was supported by Grants AR-30692 and AR-41492 from
the National Institutes of Health, a grant from The Gallagher Professorship for Arthritis Research, and funds from the
Veterans Administration Research Service.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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