It
is well known that glucocorticoids (e.g., dexamethasone, methylprednisolone, prednisone)
cause increases in the white blood cell (WBC) count.1-9 Upon further
evaluation of the increased WBC count, it is an increase in neutrophils that
primarily contribute to this effect. In addition, it is known that of all
of the mechanisms for glucocorticoid induced increases in neutrophils, it is
their demargination from the endovascular lining of the blood vessel that
predominates. Upon demargination, neutrophils are then distributed into
the general blood circulation where they can now show up in the venipuncture
sample drawn in a standard lab analysis of a patient's WBC count. This
increase in the WBC count does not occur immediately following the
administration of glucocorticoids in a patient, however this effect is known to
manifest within 5-24 hours following administration and can persist during
therapy.2,6
Why
does the increase in WBC count manifest after 5-24 hours versus immediately?
In order to understand why this biologic effect is not
immediate, an understanding of the neutrophil's process for traveling along the
endothelial lining of a blood vessel (i.e., within the marginal compartment) is
needed. Immature (bands) and mature (segmented) neutrophils both express
a cell surface adhesion molecule called L-selectin (CD26L).10,11 This
adhesion molecule is known to contribute to the formation of temporary
carbohydrate-protein bonds on the surface of the endothelial cells lining the
blood vessel wall. The selectin adhesion molecules do not interact
as tightly with the protein molecules on the endothelial surfaces and thus,
allow for their ability to roll fast along the surface until alerted to
transmigrate into the tissue to fight an infection.10,11 As such,
L-selectins are known to undergo rapid turnover as they roll along the endothelial
surface.12,13 In fact, the L-selectins are constantly being cleaved by
membrane-associated cysteine metalloproteinase (also known as sheddase).12,13 The
replacement of L-selectin to 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.6 If this does not occur, then the
neutrophil's temporary or loosely bound carbohydrate-protein bonds are not
sufficient to keep the neutrophil attached to the endothelial surface and thus,
undergoes demargination into the circulatory compartment.6 It is the
inhibition of gene transcription for L-selectin by glucocorticoids that results
in the ability of the neutrophil to push newly formed L-selectin to the cell
surface to replace the constant shedding of L-selectin by sheddase.6 The
process of inhibiting gene transcription is not immediate and generally lags
behind the initial pharmacologic effect of the medication. The average
time for this biologic effect to start to manifest on the WBC count has been
shown to be between 5-24 hours.2,6 If glucocorticoids were to offer
an immediate effect on neutrophil demargination they would likely activate
sheddase, which has been shown to not be the case.14 Therefore, the
surface cell adhesion protein, L-selectin is not being replaced and thus can no
longer interact with the endothelium of the blood vessel.
Therefore,
due to the small delay from the inhibition of gene transcription/translation
for the production of new L-selectin, the increase WBC counts will not manifest
for several hours post-administration of glucocorticoids. While this may
happen, the magnitude of the increase or effect seen may be influenced by the
time the WBC is obtained from the patient in relation to the initial dosing of
glucocorticoids, as well as when follow up labs are done.
References:
- Abramson N, Melton B. Leukocytosis: basic of clinical assessment. Am Fam Physician 2000;62:2053-60.
- Shoenfeld
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.
- Nakagawa
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.
- Burton
JL, Kehrli ME Jr, Kapil S et al. Regulation of L-selectin and CD18 on
bovine neutrophils by glucocorticoids: effects of cortisol and
dexamethasone. J Leukoc Biol 1995;57:317-25.
- Waisman
D, Van Eeden SF, Hogg JC et al. L-selectin expression on
polymorphonuclear leukocytes and monocytes in premature infants: reduced
expression after dexamethasone treatment for bronchopulmonary
dysplasia. J Pediatr 1998;132:53-6.
- Weber
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.
- Liles WC, Dale DC, Klebanoff SJ. Glucocorticoids inhibit apoptosis of human neutrophils. Blood 1995;86:3181-8.
- Cox
G. Glucocorticoid treatment inhibits apoptosis in human neutrophils.
Separation of survival and activation outcomes. J Immunol
1995;154:4719-25.
- Bishop
CR, Athens JW, Boggs DR et al. Leukokinetic studies. 13. A
non-steady-state kinetic evaluation of the mechanism of
cortisone-induced granulocytosis. J Clin Invest 1968;47:249-60.
- Tedder TF, Steeber DA, Chen A et al. The selectins: vascular adhesion molecules. FASEB J 1995;9:866-73.
- Van
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.
- Preece
G, Murphy G, Ager A. Metalloproteinase-mediated regulation of
L-selectin levels on leucocytes. J Biol Chem 1996;271:11634-40.
- Peschon
JJ, Slack JL, Reddy P et al. An essential role for ectodomain shedding
in mammalian development. Science 1998;282:1281-4.
- Strausbaugh
HJ, Rosen SD. A potential role for annexin 1 as a physiologic mediator
of glucocorticoid-induced L-selectin shedding from myeloid cells. J
Immunol 2001;166:6294-300.
