Departments of Clinical Pharmacology and Transfusion Medicine,
The Adhesion Research Group Elaborating Therapeutics,
Vienna University Hospital School Medicine,
Vienna, Austria
To the Editor:
We read with interest the paper by Filep et al,1
who showed that dexamethasone attenuated the downregulation
of L-selectin expression induced by platelet activating
factor while not affecting basal expression of L-selectin on
neutrophils. They discuss that the "results appear to differ from
those of Burton et al, who found that in vivo glucocorticoid treatment
induced significant downregulation of both L-selectin and
CD18 expression on resting bovine neutrophils. However, these effects
of glucocorticoids became detectable only 8 to 16 hours and 2 to 3 days
after treatment, respectively. The delayed response, combined with the
fact that neutrophils reside in the peripheral blood for
only a few hours, would suggest that in cows glucocorticoids affected
neutrophil precursors in bone marrow rather than circulating
neutrophils."
Similar to the results from previous studies in
cattle2 and in rats,3 we
have recently found that dexamethasone also downregulates
basal L-selectin expression on neutrophils in humans, with a lag time
of 8 hours.4 However, this need not necessarily
be due to an effect of dexamethasone on neutrophil
precursors, because neutrophils recently released from the bone marrow
may exhibit even higher levels of L-selectin
expression.5 Also, the neutrophil half-life is
significantly prolonged when glucocorticoids are
administered,6 and L-selectin seems to decrease
on aged neutrophils.7 Therefore, it is
conceivable that downregulation of L-selectin expression by a direct or
indirect mechanism could occur on circulating neutrophils and could
also account in part for the increase in neutrophil half-life, or vice
versa.
While in vitro studies can precisely define possible effector
mechanisms, such as the marked inhibitory action of
dexamethasone on leukotriene
B4 production,1
they often do not allow extrapolation to describe the complexity of in
vivo situations. Thus, these in vitro and in vivo studies should be
regarded as complementary rather than contradictory.
References
Research Center,
Maisonneuve-Rosemont Hospital,
Department of Medicine,
University of Montréal,
Montréal, Québec, Canada
We thank Drs Jilma and Stohlawetz for their interest in our
work.1 Their concern about our discussion on the
possible effects of dexamethasone on neutrophil precursors
is based on a misreading of our article. We did not claim that
downregulation of L-selectin expression on circulating neutrophils in
cattle2 can be exclusively attributed to an
effect of dexamethasone on neutrophil precursors. Instead,
we have suggested this action as a possible explanation for the
apparently different results obtained in the study of Burton et
al2 and in our in vitro study. The statement that
Dr Jilma and colleague make concerning the direct effect of
glucocorticoids on neutrophils is somewhat controversial. Actually,
this point is more difficult for us, since we did not have an
opportunity to preview their manuscript before its publication. It is
not clear how they assessed direct effects of glucocorticoids on
neutrophils in humans. In particular, we wonder about a lag time of 8
hours. It is well established that glucocorticoids produce their effect
on responsive cells by binding to cytoplasmic glucocorticoid
receptors.3 The hormone-receptor complex then
translocates to the nucleus and modulates transcription of specific
target genes.3 4 Glucocorticoid-induced de novo
protein synthesis occurs within 1 to 3 hours, which would
certainly not explain a lag time of 8 hours. There is also some
evidence for direct effects of glucocorticoids on the function and
composition of plasma membrane of target cells, but again, the maximal
effects can be observed after 6 hours of incubation with
glucocorticoids.5 High concentrations of
glucocorticoids have been implied in stabilizing cell
membranes,6 which can be expected to inhibit
rather than facilitate L-selectin shedding.
L-selectin shedding occurs within minutes of cell
activation7 or treatment of leukocytes with
certain nonsteroidal antiinflammatory drugs8 or
C-reactive protein,9 which does not
activate leukocytes. Inasmuch as the proteolytic enzyme
("sheddase") appears to be a constitutively active enzyme, the
formation of an appropriate three-dimensional structure of L-selectin
protein near the membrane would regulate this proteolytic
processing.10 11 Although the enzymes and
signaling mechanisms that regulate the cleavable conformation of
L-selectin remain key areas of inquiry, activation of these mechanisms
requires few minutes rather than several hours.
In regard to the effects of glucocorticoids on neutrophil precursors,
the following should be considered. In humans, L-selectin expression
increases on bone marrow granulocytes with cell maturation, and mature
neutrophils recently released from the bone marrow express the highest
level of L-selectin.12 Burton et
al2 have observed "modest but significant
increases in circulating immature neutrophils" in
dexamethasone-treated cows. Since these immature cells
express less L-selectin than mature cells, it is plausible to assume
that overall decreases in neutrophil L-selectin expression (measured as
mean fluorescence staining intensity) could be detected when
considerable portions of mature neutrophils have been removed from the
circulation and/or when the aging-related shedding of
L-selectin13 is augmented. While prolongation of
the half-life of circulating neutrophils by
glucocorticoids14 is consistent with
further decreases in L-selectin expression,
dexamethasone-induced drop-off of neutrophils (which
express unknown levels of L-selectin) from the marginating
pool2 would further complicate this picture. It
should be noted that O'Leary et al15 studied
neutrophil L-selectin expression after treatment of rats with
dexamethasone for 3 days (about 6x the
dexamethasone-prolonged half-life of neutrophils). We have
not discussed these actions in detail in our article, for we have not
studied neutrophil kinetics.
Finally, while we do not agree that our report treats in vitro and in
vivo studies as contradictory, we certainly agree that both in vivo and
in vitro studies are necessary to investigate the mechanisms and the
complexity of the actions of glucocorticoids. This was perhaps omitted
from our text because it seemed obvious.
References
© 1998 American Heart Association, Inc.
Correspondence
Dexamethasone Downregulates L-Selectin In Vitro and In Vivo
Response
This article has been cited by other articles:
 |
|
 |
|
  P. S. D. Weber, T. Toelboell, L.-C. Chang, J. D. Tirrell, P. M. Saama, G. W. Smith, and J. L. Burton Mechanisms of glucocorticoid-induced down-regulation of neutrophil L-selectin in cattle: evidence for effects at the gene-expression level and primarily on blood neutrophils J. Leukoc. Biol., May 1, 2004; 75(5): 815 - 827. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||