Partial mediation of glucocorticoid antiproliferative effects by lipocortins.
The glucocorticoids (GCs) dexamethasone (DEX) and prednisolone (PRED), in a concentration-dependent fashion, profoundly inhibit mitogen-induced proliferation of human peripheral blood mononuclear lymphocytes (PBML). This inhibition was specific for GCs, as non-GC steroids were devoid of any antiproliferative capacity. GCs enhanced the mRNA (Northern blot) and protein (Western blot) expression of the calcium and phospholipid binding proteins lipocortin I, II, and V. As a consequence of mitogenic stimulation, PBML secrete PGE2 and leukotriene B4 (LTB4). Antiproliferative concentrations of both DEX and PRED as well as recombinant lipocortin I abolished PGE2 and LTB4 production, suggesting an involvement of lipocortins in GC-mediated antiproliferative effects, possibly by inhibiting eicosanoid production and, consequently, mitogen-induced cellular proliferation. Whereas 5,8,11,14-eicosatetraynoic acid and nordihydroguaiaretic acid mimicked DEX and PRED in inhibiting PGE2 and LTB4 production, neither 5,8,11,14-eicosatetraynoic acid nor nordihydroguaiaretic acid had any effect on mitogen-induced PBML proliferation, indicating that the GC-mediated antiproliferative effect is separate from their effects on eicosanoid release. Furthermore, neutralizing anti-lipocortin I and anti-lipocortin II mAb, while reversing the inhibitory activity of DEX and PRED on PGE2 and LTB4 production, only partially reversed DEX- and PRED-mediated antiproliferative effects. This indicates that the GC-mediated antiproliferative effect is not dependent on inhibition of eicosanoid release by lipocortins and suggests the existence of lipocortin-dependent and lipocortin-independent pathways by which GCs mediate their antiproliferative effects.
Almawi
W Y
WY
Department of Biochemistry, Faculty of Medicine, American University of Beirut, Lebanon.
Saouda
M S
MS
Stevens
A C
AC
Lipman
M L
ML
Barth
C M
CM
Strom
T B
TB
D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D017302:Annexins / Q000502:physiology*; D016718:Arachidonic Acid / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects*; D009637:Masoprocol / Q000494:pharmacology; D011239:Prednisolone / Q000494:pharmacology
D017302:Annexins; D005938:Glucocorticoids; D015117:5,8,11,14-Eicosatetraynoic Acid; D016718:Arachidonic Acid; D009637:Masoprocol; D003907:Dexamethasone; D011239:Prednisolone; D006854:Hydrocortisone