Mechanism of action of glucocorticosteroids. Inhibition of T cell proliferation and interleukin 2 production by hydrocortisone is reversed by leukotriene B4.

Abstract

The mechanism whereby glucocorticosteroids are immunosuppressive is unknown. One potential mechanism of action of these compounds is inhibition of arachidonic acid metabolism. We found that the inhibition of lymphocyte proliferation by hydrocortisone or dexamethasone was mimicked by nonspecific lipoxygenase inhibitors and also by a specific 5-lipoxygenase inhibitor, but not by a specific cyclooxygenase inhibitor. Mitogen-stimulated cultures of T cells produce -5 X 10-9 M leukotriene B4 (LTB4) in 24 h. This production of LTB4 is completely inhibited by concentrations of hydrocortisone or lipoxygenase inhibitors that inhibit mitogen-induced VHjthymidine incorporation. The inhibition of lymphocyte proliferation by either hydrocortisone or by the 5-lipoxygenase inhibitor was totally reversed by LTB4 but not by leukotriene C4 or leukotriene D4. LTB4 had no effect on the inhibition of lymphocyte proliferation by noncorticosteroids such as prostaglandin E2, histamine, or y-interferon. The inhibition of interleukin 2 (IL-2) production by hydroccrtisone or dexamethasone was also completely reversed by exogenous LTB4.

Synthesis of hydroxyeicosatetraenoic acids and leukotrienes in rat nephrotoxic serum glomerulonephritis. Role of anti-glomerular basement membrane antibody dose, complement, and neutrophiles.

“…A23187 (2 uM) induced significant production of these two eicosanoids in the low-dose group. However, their levels (all in ng/mg glomerular protein) were not statistically different from respective controls (5-HETE, 12 4.4 Values reflect the mean of duplicate observations. cantly higher levels by 24 h when significant PMN infiltration was still present (3.2±0.4).…”

Role of nicotinamide adenine dinucleotide and adenosine triphosphate in glucocorticoid-induced cytotoxicity in susceptible lymphoid cells.

“…Obviously, steroid-induced cell death would interfere with the ability of the dead lymphocyte to participate in the immune response. However, it has been shown recently that steroids can interfere with the immune response by inhibiting production ofleukotriene B4 in mitogen-stimulated lymphocytes (21). Thus, interference with arachidonic acid metabolism may produce a pathway for inhibiting the immune response without causing cell death.…”

Effects of monocyte‐lymphocyte interaction on the synthesis of leukotriene B4

“…In contrast to these studies, other investigators have reported that lymphocytes have the capacity to synthesize 5-hydroxyeicosatetraenoic acid and leukotrienes from arachidonic acid [37,38]. However, one of these groups has not been able to confirm their initial findings [lo].…”