Mertz P M, Corcoran M L, McCluskey K M, Zhang Y, Wong H L, Lotze M T, DeWitt D L, Wahl S M, Wahl L M
Laboratory of Immunology, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Cell Immunol. 1996 Nov 1;173(2):252-60. doi: 10.1006/cimm.1996.0275.
IL-4 is a potent modulator of monocyte function. Our previous studies demonstrated that the suppression of monocyte matrix metalloproteinase production by IL-4 is a result of its inhibition of PGE2 synthesis, which was attributed to an effect on prostaglandin synthase. Here we report on the in vitro and in vivo effects of IL-4 on monocyte prostaglandin H synthase-2 (PGHS-2) and its regulation by second messengers. Stimulation of monocytes with either LPS or Con A resulted in the induction of PGHS-2 which was significantly inhibited by IL-4. Inhibition of PGHS-2 mRNA and protein was detected at 0.05 to 0.1 ng/ml of IL-4 with substantial suppression at 10 to 20 ng/ml. If added later than 2 hr after LPS, IL-4 failed to suppress PGHS-2, indicating that IL-4 acted early in the signaling cascade. Moreover, the ability of exogenously added PGE2 or Bt2cAMP to restore PGHS-2 production in IL-4-treated monocytes further suggested early disruption of the pathway. The early event inhibited by IL-4 did not involve suppression of phospholipase activity, because LPS-induced arachidonic acid release was relatively unaffected by IL-4. Unlike PGHS-2, PGHS-1, the constitutively expressed PGHS, was not modulated by IL-4. Thus, IL-4 appears to selectively block PGHS-2 synthesis, thereby blocking subsequent steps in the pathway leading to the production of matrix metalloproteinases. In an extension of these findings, we examined peripheral blood monocytes from cancer patients undergoing IL-4 therapy. In these cells the induction of PGHS-2 expression by LPS was significantly reduced compared to that of monocytes obtained prior to IL-4 therapy. Although perhaps not relevant as an antitumor mechanism, these findings have important implications in defining the potent anti-inflammatory activities of IL-4 in vitro and in vivo.
白细胞介素-4是单核细胞功能的强效调节剂。我们之前的研究表明，白细胞介素-4对单核细胞基质金属蛋白酶产生的抑制作用是其抑制前列腺素E2合成的结果，这归因于对前列腺素合酶的影响。在此，我们报告白细胞介素-4对单核细胞前列腺素H合酶-2（PGHS-2）的体外和体内作用及其受第二信使的调节。用脂多糖（LPS）或刀豆蛋白A（Con A）刺激单核细胞会导致PGHS-2的诱导，而白细胞介素-4可显著抑制这种诱导。在0.05至0.1纳克/毫升的白细胞介素-4浓度下可检测到PGHS-2 mRNA和蛋白的抑制，在10至20纳克/毫升时抑制作用显著。如果在LPS刺激后2小时后添加白细胞介素-4，则无法抑制PGHS-2，这表明白细胞介素-4在信号级联反应的早期起作用。此外，外源性添加前列腺素E2或双丁酰环磷腺苷（Bt2cAMP）以恢复白细胞介素-4处理的单核细胞中PGHS-2产生的能力进一步表明该途径的早期破坏。白细胞介素-4抑制的早期事件不涉及磷脂酶活性的抑制，因为LPS诱导的花生四烯酸释放相对不受白细胞介素-4的影响。与PGHS-2不同，组成性表达的PGHS-1不受白细胞介素-4的调节。因此，白细胞介素-4似乎选择性地阻断PGHS-2的合成，从而阻断导致基质金属蛋白酶产生的途径中的后续步骤。在这些发现的扩展研究中，我们检查了接受白细胞介素-4治疗的癌症患者的外周血单核细胞。与白细胞介素-4治疗前获得的单核细胞相比，这些细胞中LPS诱导的PGHS-2表达明显降低。尽管这些发现可能与抗肿瘤机制无关，但它们在确定白细胞介素-4在体外和体内的强效抗炎活性方面具有重要意义。
