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Immunology Research Group and Departments of Physiology and Biophysics and Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1
Although known for its role
in hemostasis, there is a growing body of evidence that thrombin can
induce leukocyte recruitment and contribute to the inflammatory
response. An in vitro parallel-plate flow chamber was used to
systematically examine thrombin-induced neutrophil interactions with
human endothelium. Stimulation of endothelial cells with thrombin (1 U/ml) resulted in an immediate, P-selectin-dependent increase in
neutrophil rolling and adhesion that was comparable in magnitude to
optimal levels of histamine (the classical inducer of P-selectin).
However, thrombin, but not histamine, induced a delayed (4 h)
E-selectin-dependent rolling similar to that of tumor
necrosis factor-
, suggesting that thrombin has the unique ability to
recruit neutrophils by an early P-selectin and a delayed E-selectin
pathway. Surprisingly, inhibition of E-selectin expression with the
general protein synthesis inhibitor cycloheximide induced P-selectin
expression 4 h after thrombin stimulation. Cycloheximide and thrombin
(4 h) induced sufficient P-selectin-dependent rolling to recruit as
many neutrophils as were recruited with 4 h of stimulation with
thrombin alone. Histamine in the presence of cycloheximide or
cycloheximide alone did not evoke the P-selectin response at 4 h,
suggesting that this was not due to direct cycloheximide induction of
P-selectin. Treatment of endothelium with tumor necrosis factor- (an
E-selectin inducer) and cycloheximide also eliminated E-selectin
expression but, much like thrombin, induced P-selectin expression and
neutrophil recruitment. In conclusion, inhibition of E-selectin via
protein synthesis inhibition activates the protein
synthesis-independent pathway of P-selectin expression to support
adequate leukocyte recruitment.
leukocytes; endothelium; adhesion molecules; thrombin; tumor necrosis factor
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