Modulation of leukotriene B4 receptor-1 expression by dexamethasone: potential mechanism for enhanced neutrophil survival.
Glucocorticoids can down-regulate many inflammatory and immune responses and constitute a powerful therapeutic tool in a number of diseases. However, they have a somewhat paradoxical effect on neutrophils, in that they prolong their survival. Because leukotriene B(4) (LTB(4)) can also extend neutrophil survival, we proposed that glucocorticoids could prevent neutrophil apoptosis by up-regulating their expression of the high-affinity LTB(4) receptor (BLT1). Here we show that, indeed, dexamethasone (DEX) up-regulates the steady-state levels of BLT1 mRNA in human neutrophils. The effect was time and concentration dependent, being maximal at 4 h and at 10-100 nM DEX. The effect was also dependent on transcriptional activity, whereas BLT1 mRNA stability was not affected. DEX-induced up-regulation of BLT1 expression was prevented by pretreatment with the LTB(4) antagonist LY255283. Moreover, LTB(4) itself up-regulated the expression of BLT1 mRNA. BLT1 protein expression on neutrophils exposed to DEX for 24 h was also up-regulated 2- to 3-fold, and DEX-treated as well as LTB(4)-treated cells showed enhanced responsiveness to LTB(4) in terms of intracellular Ca(2+) mobilization and chemotaxis. Whereas DEX and LTB(4) alone decreased neutrophil apoptosis by approximately 50%, neutrophils treated with both LTB(4) and DEX showed >90% survival at 24 h. Moreover, BLT1 antagonists prevented the increased neutrophil survival induced by DEX as well as by LTB(4). Taken together, our results suggest that DEX-induced up-regulation of BLT1 expression in neutrophils may be one mechanism through which glucocorticoids can prolong neutrophil survival, namely by enhancing cell responses to the antiapoptotic effect of LTB(4).
Stankova
Jana
J
Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Turcotte
Sylvie
S
Harris
Jennifer
J
Rola-Pleszczynski
Marek
M
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D005233:Fatty Alcohols / Q000494:pharmacology; D005434:Flow Cytometry; D006018:Glycols / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D005233:Fatty Alcohols; D006018:Glycols; D012333:RNA, Messenger; D018102:Receptors, Leukotriene B4; D013777:Tetrazoles; C062137:U 75302; D003609:Dactinomycin; D007975:Leukotriene B4; D003907:Dexamethasone; C063823:LY 255283; D002118:Calcium