MECHANISM OF ACTION OF GLUCOCORTICOSTEROIDS - INHIBITION OF T-CELL PROLIFERATION AND INTERLEUKIN-2 PRODUCTION BY HYDROCORTISONE IS REVERSED BY LEUKOTRIENE-B4
MECHANISM OF ACTION OF GLUCOCORTICOSTEROIDS - INHIBITION OF T-CELL PROLIFERATION AND INTERLEUKIN-2 PRODUCTION BY HYDROCORTISONE IS REVERSED BY LEUKOTRIENE-B4
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DOI：
10.1172/jci112427
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发表时间：
1986-04-01
影响因子：
15.9
通讯作者：
LIANOS, EA
中科院分区：
文献类型：
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作者：
GOODWIN, JS;ATLURU, D;LIANOS, EA
糖皮质激素的免疫抑制机制尚不清楚。这些化合物的一种潜在作用机制是抑制花生四烯酸代谢。我们发现，淋巴细胞增殖的抑制氢化可的松或地塞米松是模仿非特异性脂氧合酶抑制剂，也由一个特定的5-脂氧合酶抑制剂，但不是由一个特定的环氧合酶抑制剂。T细胞的促分裂原刺激培养物产生. apprx。5倍。10-9 M白三烯B_4（LTB_4）。这种LTB 4的产生被抑制有丝分裂原诱导的[3 H]胸苷掺入的氢化可的松或脂氧合酶抑制剂的浓度完全抑制。淋巴细胞增殖的抑制氢化可的松或5-脂氧合酶抑制剂被完全逆转LTB 4，但不是由白三烯C4或白三烯D4。LTB 4对非皮质类固醇如前列腺素E2、组胺或γ-肾上腺素抑制淋巴细胞增殖没有作用。干扰素氢化可的松或地塞米松对白细胞介素2（IL-2）产生的抑制作用也可被外源性LTB 4完全逆转。LTB 4沿着加入静息淋巴细胞时，不引起IL-2产生或细胞增殖。因此，内源性LTB 4的产生似乎是必要的，但不足以植物血凝素诱导的IL-2的生产和淋巴细胞增殖。糖皮质激素通过抑制内源性LTB 4的产生来抑制IL-2的产生和淋巴细胞增殖。
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 .apprx. 5 .times. 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 [3H]thymidine 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 .gamma.-interferon. The inhibition of interleukin 2 (IL-2) production by hydrocortisone or dexamethasone was also completely reversed by exogenous LTB4. LTB4 along did not cause IL-2 production or cell proliferation when added to resting lymphocytes. Thus, endogenous LTB4 production appears to be necessary but not sufficient for phytohemagglutinin-induced IL-2 production and lymphocyte proliferation. Glucocorticosteroids inhibit IL-2 production and lymphocyte proliferation by inhibiting endogenous LTB4 production.