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Blood, 1 June 2001, Vol. 97, No. 11, pp. 3433-3440
HEMATOPOIESIS
Chemotaxis and transendothelial migration of CD34+
hematopoietic progenitor cells induced by the inflammatory mediator
leukotriene D4 are mediated by the 7-transmembrane
receptor CysLT1
Frank Bautz,
Claudio Denzlinger,
Lothar Kanz, and
Robert Möhle
From the Department of Medicine II, University of
Tübingen, Germany.
Recent studies suggest that bone marrow (BM)-derived chemotactic
mediators such as chemokines play key roles in hematopoietic stem cell
trafficking. Lipid mediators, particularly leukotrienes, are involved
in leukocyte chemotaxis during inflammation but have also been detected
in the normal BM. Therefore, the effects of leukotrienes on
hematopoietic progenitor cells were analyzed. Cysteinyl leukotrienes,
particularly leukotriene D4 (LTD4), induced strong intracellular
calcium fluxes and actin polymerization in mobilized and BM
CD34+ progenitors. Chemotaxis and in vitro transendothelial
migration of CD34+ and more primitive
CD34+/CD38 cells were 2-fold increased by
LTD4 at an optimum concentration of 25 to 50 nM. Accordingly,
CD34+ cells expressed the 7-transmembrane LTD4 receptor
CysLT1 by reverse transcriptase-polymerase chain reaction and Western
blot. Effects of LTD4 were suppressed by the CysLT1 receptor antagonist
MK-571 and reduced by pertussis toxin. In contrast, LTB4 induced strong responses only in mature granulocytes. LTD4-induced calcium fluxes were
also observed in granulocytes but were not reduced by MK-571, suggesting that these effects were mediated by other receptors (eg,
CysLT2) rather than by CysLT1. In addition, expression of 5-lipoxygenase, the key enzyme of leukotriene biosynthesis, was detected in both hematopoietic progenitor cells and mature leukocytes. The study concludes that the functionally active LTD4 receptor CysLT1
is preferentially expressed in immature hematopoietic progenitor cells.
LTD4 released in the BM might regulate progenitor cell trafficking and
could also act as an autocrine mediator of hematopoiesis. This would be
a first physiologic effect of cysteinyl leukotrienes apart
from the many known pathophysiologic actions related to allergy and inflammation.
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