Pre-translational regulation of neutrophil L-selectin in glucocorticoid-challenged cattle

L-selectin (CD62L) gene expression in neutrophils is commonly referred to a s "constitutive" because circulating neutrophils require a constant supply of this adhesion molecule for continuous trafficking into peripheral tissue s. Under normal circumstances, marginating blood neutrophils and neutrophil s that become activated for migration into infected tissues rapidly shed su rface CD62L that is ligated to the vascular endothelium. However, this does not shut down CD62L gene expression because these cells continue to expres s surface CD62L. In contrast, glucocorticoid challenges resulting from stre ss and hormone injections result in gradual and chronic downregulation of C D62L on the surface of blood neutrophils. Rather than being associated with migration, this type of CD62L down-regulation associates with pronounced n eutrophilia and increased susceptibility to infections. Nothing is currentl y known about glucocorticoid regulation of CD62L expression in neutrophils. In other cell systems, however, this steroid hormone binds to cytoplasmic glucocorticoid receptors (GR) that influence expression of glucocorticoid-r esponsive genes at multiple pre-translational levels. Thus, the hypothesis of the present study was that glucocorticoid challenge suppresses CD62L mRN A expression in blood neutrophils. Suppressed CD62L gene expression might h elp explain the chronic down-regulation of surface CD62L in neutrophils and accompanying neutrophilia. The main objectives of the study were to monito r neutrophil CD62L mRNA abundance before and during subtle and severe gluco corticoid challenges and to determine if CD62L mRNA expression correlates w ith degree of glucocorticoid challenge. Parturient dairy cows and dexametha sone-treated steers were used as models of subtle and severe (respectively) glucocorticoid challenges. Data presented from both models support the hyp othesis and show for the first time that glucocorticoids regulate neutrophi l CD62L at a pre-translational level. Results also. showed that inhibited C D62L mRNA expression correlated precisely with downregulated surfaced expre ssion of CD62L on neutrophils and peak neutrophilia during. severe glucocor ticoid challenge. Therefore, results of this study indicate that bovine neu trophils are highly sensitive to the blood environment, displaying full cap acity to alter CD62L gene expression. and trafficking patterns in response to changing glucocorticoid levels. This may serve animals, well when height ened inflammatory responses begin to lead to tissue damage, but may be detr imental to overall health if animals are exposed to opportunistic pathogens while stressed or undergoing glucocorticoid therapy. Although this study d id not elucidate how glucocorticoids inhibit neutrophil CD62L mRNA expressi on, presented data implicate GR as possibly being involved because neutroph ils from cattle in both models expressed GR mRNA. Further in vitro studies using purified populations of neutrophils; will be required to determine if GR is directly involved in glucocorticoid regulation of CD62L gene express ion and, if so, at what level. (C) 2001 Elsevier Science B.V. All rights, r eserved.