Pincus S H, Whitcomb E A, Dinarello C A
J Immunol. 1986 Dec 1;137(11):3509-14.
The tumor co-promotor TPA is believed to enhance a wide variety of cellular processes by interacting with protein kinase C. Interleukin (IL 1) is a family of highly active molecules which augments the host response to infection. We have explored the interactions of these activators of cell function on the modulation of selected eosinophil functions. The effects of purified monocyte-derived IL 1 on the eosinophil functions of oxidative metabolism (as measured by superoxide anion production) and degranulation (as measured by release of the granular enzymes arylsulfatase and beta-glucuronidase) have been examined. Superoxide anion production by eosinophils stimulated with standard doses of the stimulant phorbol myristic acetate (TPA) (1 microgram/ml) was augmented approximately 20% by preincubation with IL 1. However, IL 1 alone had no effect on superoxide anion production. At suboptimal doses of TPA, there was a dose-dependent inhibition of superoxide anion production in the presence of IL 1. Calcium ionophore (2 X 10(-7) M) markedly enhanced superoxide anion production elicited by 0.1 ng/ml of TPA, but had only modest effects in the absence of TPA. When IL 1 was added to eosinophils stimulated by TPA in the presence of calcium ionophore, there was a dose-dependent increase in superoxide anion production. In contrast to other cell types, degranulation as measured by the release of arylsulfatase and beta-glucuronidase was not elicited by the addition of TPA (1 microgram/ml). Although calcium ionophore (2 X 10(-6) M) caused enzyme release (24.2% release of beta-glucuronidase, 29.4% release of arylsulfatase), this release was inhibited by the addition of TPA. The addition of IL 1 alone caused an approximate twofold increase in enzyme release, but pretreatment with IL 1 (1 U) reduced ionophore-mediated degranulation (p less than or equal to 0.05). Studies employing purified monocyte IL 1 were confirmed by recombinant IL 1-beta. These studies demonstrate for the first time that eosinophil function is modulated by IL 1. IL 1 may also modify the response of eosinophils to other stimuli such as ionophore and TPA. Because TPA is known to act by direct binding to protein kinase C, these studies also demonstrate that, in eosinophils, activation of protein kinase C by phorbol esters may augment one cellular function (oxidative metabolism) while inhibiting another cellular function (degranulation). Similarly, phorbol esters may act synergistically with calcium ionophore in regulation of one function (oxidative metabolism) and act antagonistically with another function (degranulation). The concept that IL 1 uniformly enhances cell function may need to be re-evaluated.
肿瘤协同促进剂佛波酯（TPA）被认为可通过与蛋白激酶C相互作用来增强多种细胞过程。白细胞介素（IL - 1）是一类高活性分子家族，可增强宿主对感染的反应。我们探究了这些细胞功能激活剂在调节特定嗜酸性粒细胞功能方面的相互作用。已检测了纯化的单核细胞衍生IL - 1对嗜酸性粒细胞氧化代谢功能（通过超氧阴离子产生来衡量）和脱颗粒功能（通过颗粒酶芳基硫酸酯酶和β - 葡萄糖醛酸酶的释放来衡量）的影响。用标准剂量的刺激物肉豆蔻酸佛波醇酯（TPA）（1微克/毫升）刺激嗜酸性粒细胞后，预先用IL - 1孵育可使超氧阴离子产生增加约20%。然而，单独的IL - 1对超氧阴离子产生没有影响。在TPA剂量不足时，在有IL - 1存在的情况下超氧阴离子产生呈剂量依赖性抑制。钙离子载体（2×10⁻⁷ M）显著增强了由0.1纳克/毫升TPA引发的超氧阴离子产生，但在没有TPA时作用较小。当在有钙离子载体存在的情况下将IL - 1添加到由TPA刺激的嗜酸性粒细胞中时，超氧阴离子产生呈剂量依赖性增加。与其他细胞类型不同，添加TPA（1微克/毫升）不会引发通过芳基硫酸酯酶和β - 葡萄糖醛酸酶释放来衡量的脱颗粒。尽管钙离子载体（2×10⁻⁶ M）导致酶释放（β - 葡萄糖醛酸酶释放24.2%，芳基硫酸酯酶释放29.4%），但添加TPA可抑制这种释放。单独添加IL - 1可使酶释放增加约两倍，但用IL - 1（1单位）预处理可减少离子载体介导的脱颗粒（p≤0.05）。使用纯化的单核细胞IL - 1的研究得到了重组IL - 1 - β的证实。这些研究首次证明IL - 1可调节嗜酸性粒细胞功能。IL - 1也可能改变嗜酸性粒细胞对其他刺激物如离子载体和TPA的反应。由于已知TPA通过直接与蛋白激酶C结合起作用，这些研究还表明，在嗜酸性粒细胞中，佛波酯激活蛋白激酶C可能增强一种细胞功能（氧化代谢），同时抑制另一种细胞功能（脱颗粒）。同样，佛波酯在调节一种功能（氧化代谢）方面可能与钙离子载体协同作用，而在另一种功能（脱颗粒）方面则起拮抗作用。IL - 1一致增强细胞功能的概念可能需要重新评估。
