The general review of causes and mechanisms that contribute to glucocorticoid induced leukocytosis (increase
in white blood cell (WBC) counts) can be found in this EBM Consult article ... click here.1 Of the
mechanisms contributing to the increase in WBC counts, the demargination of
neutrophils (polymorphonuclear leukocytes; PMN) from the endothelial lining of
the blood vessels into the general circulation is most significant.2 In
fact, approximately 61% of the increase in WBC counts comes from this biologic
effect of glucocorticoid use and can be observed within 5-24 hours of
do glucocorticoids (e.g., dexamethasone, methylprednisolone, prednisone) effect
neutrophils (PMN) to cause this demargination?
Neutrophils reside in a number of compartments; the two compartments related to
this issue are the marginal compartment (those neutrophils attached to the
endothelium of the blood vessel) and the circulating compartment (those
circulating in the blood vessels along with other cells).5 This
distinction is important as neutrophils traveling on the endothelial surface
within the lumen of the blood vessel (i.e., in the marginal compartment) are
not reflected in a WBC count. Only the PMN freely circulating within the
circulatory compartment will be found in the venous sample used for
analysis. As such anything that causes the marginal neutrophils to detach
from the endothelial surface of the blood vessel wall will result in a greater
concentration of neutrophils in the circulatory compartment and thus increase
the WBC count. Glucocorticoids are known to do this.2-4
(both bands and segs) normally express a cell surface adhesion molecule called
L-selectin (CD26L) that is known to contribute to the formation of temporary
carbohydrate-protein bonds on the surface of the endothelial cells lining the
blood vessel wall.6,7 The selectin adhesion molecules do not interact
tightly with the protein molecules on the endothelial surfaces which explains
the neutrophil's ability to roll quickly along the surface until alerted to
transmigrate into the tissue to fight an infection.6,7 L-selectin is
known to undergo rapid turnover as the neutrophils roll along the endothelial
surface.8,9 In fact, the L-selectin are constantly being cleaved by
membrane-associated cysteine metalloproteinase (also known as sheddase).8,9
The replacement of L-selectin on the surface of the cell membrane is dependent
on the neutrophil's ability to undergo gene transcription to make more
L-selectin that is then translated, packaged and prepared for transport to the
cell surface to replace the shed L-selectin.4 If this does not occur,
then the number of temporary or loosely bound carbohydrate-protein bonds
will decrease and eventually not be sufficient to keep the neutrophil attached
to the endothelial surface and thus demargination into the circulatory
compartment will occur.4 Therefore, it is the inhibition of gene
transcription of L-selectin by glucocorticoids that results in L-selectin not
being replaced and thus reducing the ability of the neutrophil to interact with
the endothelium of the blood vessel.
do glucocorticoids decrease gene transcription of L-selectin thereby decreasing
the neutrophil's ability to replace shed L-selectin to maintain its attachment
to the endothelial surface?
exact details of how glucocorticoids turn off gene transcription for L-selectin
is not completely understood. However, glucocorticoids are very well known to
bind to glucocorticoid receptors (in particular GR-alpha) found in the
cytoplasm of the neutrophil.4 Upon binding, the glucocorticoid/GR complex
results in a conformational change that results in the dissociation of other
proteins that free the glucocorticoid/GR complex to enter into the
nucleus. After entering the nucleus it can bind to glucocorticoid
responsive elements (GRE) in the region just above the target gene (L-selectin
in this case) where it can either turn on gene transcription or inhibit
it. It is likely that this is where the inhibition occurs since mRNA
levels for L-selectin are decreased with glucocorticoid use.4 This
process does not occur immediately which explains why the progressive loss of
L-selectin starts 5-24 hours post administration of the glucocorticoid and
coincides with the rise in PMNs in the WBC count.
glucocorticoids are known to increase the concentration of neutrophils present
in the circulatory compartment thereby increasing the WBC count, the effect of
demargination is also one of the mechanisms involved in their antiinflammatory
properties. If the neutrophil is not attached to the endothelium,
transmigration into the tissue is decreased.
- Busti AJ, et al. A general review of the mechanisms for steroid or glucocorticoid (e.g., dexamethasone,
methylprednisolone, prednisone) increases the white blood cell (WBC)
count. EBM Consult.
M, Terashima T, D'yachkova Y et al. Glucocorticoid-induced
granulocytosis: contribution of marrow release and demargination of
intravascular granulocytes. Circulation 1998;98:2307-13.
Y, Gurewich Y, Gallant LA, et al. Prednisone-induced leukocytosis.
Influenced of dosage, method and duration of administration on the
degree of leukocytosis. Am J Med 1981;71:773-8.
PS, Toelboell T, Chang LC et al. 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 2004;75:815-27.
- Junqueira LC, Carneiro J. Blood cells. In: Basic Histology. 11th ed. Junqueira LC, Caneiro J eds. McGraw-Hill Medical Publishing Division. New York, NY. 2005; 223-237.
- Tedder TF, Steeber DA, Chen A et al. The selectins: vascular adhesion molecules. FASEB J 1995;9:866-73.
Eeden S, Miyagashima R, Haley L et al. L-selectin expression increases
on peripheral blood polymorphonuclear leukocytes during active marrow
release. Am J Respir Crit Care Med 1995;151:500-7.
G, Murphy G, Ager A. Metalloproteinase-mediated regulation of
L-selectin levels on leucocytes. J Biol Chem 1996;271:11634-40.
JJ, Slack JL, Reddy P et al. An essential role for ectodomain shedding
in mammalian development. Science 1998;282:1281-4.