Berger A E, Carter D B, Hankey S O, McEwan R N
Cell Biology Unit, Upjohn Company, Kalamazoo, MI 49008.
Eur J Immunol. 1993 Jan;23(1):39-45. doi: 10.1002/eji.1830230108.
A naturally occurring receptor-level antagonist of interleukin-1 (IRAP or IL-1 ra) has recently been cloned. To determine what stimuli might regulate this inhibitor, cytokines were tested for their effects on the steady-state level of IRAP mRNA in phorbol ester-differentiated U937 cells. The cytokines tested fell into one of three groups: (a) inducers: granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-4, (b) weak inducers (< 2-fold stimulation): [IL-1 alpha, IL-1 beta, and transforming growth factor-beta (TGF-beta)] and (c) cytokines with no effect: (IL-2, platelet-derived growth factor, acidic fibroblast growth factor, basic fibroblast growth factor, epidermal growth factor, granulocyte colony-stimulating factor, IL-3, IL-5, IL-6, interferon-gamma, multi-colony stimulating factor, tumor necrosis factor-alpha and IRAP itself. One hundred U/ml of either GM-CSF or IL-4 was the dose inducing peak IRAP mRNA expression; that peak expression occurred 12 h after addition of cytokine. GM-CSF induced a 34 +/- 15-fold increase in IRAP mRNA, and IL-4 induced a 15 +/- 6-fold increase. In the same RNA samples, GM-CSF increased IL-1 beta mRNA 5.9 +/- 1.7-fold, but IL-4 decreased IL-1 beta mRNA to half that of control levels (0.45 +/- 0.17). Thus, a single stimulus (IL-4) decreased the expression of an agonist (IL-1) while it increased the expression of an antagonist (IRAP). When U937 cells were treated with both IL-4 and GM-CSF, the level of IRAP mRNA induced was additive, suggesting that the cytokines acted differently to increase IRAP mRNA levels. The level of IL-1 mRNA in cells treated with both IL-4 and GM-CSF was intermediate. Dexamethasone and cycloheximide inhibited all mRNA increases and did not reverse IL-4-induced decreases in IL-1 mRNA. These studies have identified two cytokines which induce IRAP in the monocytic cells studied, and have partially characterized the differential regulation of IL-1 and its antagonist, IRAP.
白细胞介素-1（IRAP或IL-1 ra）的一种天然存在的受体水平拮抗剂最近已被克隆。为了确定哪些刺激可能调节这种抑制剂，检测了细胞因子对佛波酯分化的U937细胞中IRAP mRNA稳态水平的影响。所检测的细胞因子分为三组之一：（a）诱导剂：粒细胞-巨噬细胞集落刺激因子（GM-CSF）、IL-4；（b）弱诱导剂（刺激倍数<2倍）：[IL-1α、IL-1β和转化生长因子-β（TGF-β）]；（c）无作用的细胞因子：（IL-2、血小板衍生生长因子、酸性成纤维细胞生长因子、碱性成纤维细胞生长因子、表皮生长因子、粒细胞集落刺激因子、IL-3、IL-5、IL-6、干扰素-γ、多集落刺激因子、肿瘤坏死因子-α和IRAP本身）。100 U/ml的GM-CSF或IL-4是诱导IRAP mRNA表达峰值的剂量；该峰值表达在添加细胞因子后12小时出现。GM-CSF诱导IRAP mRNA增加34±15倍，IL-4诱导增加15±6倍。在相同的RNA样本中，GM-CSF使IL-1β mRNA增加5.9±1.7倍，但IL-4使IL-1β mRNA降至对照水平的一半（0.45±0.17）。因此，单一刺激（IL-4）在增加拮抗剂（IRAP）表达的同时降低了激动剂（IL-1）的表达。当U937细胞用IL-4和GM-CSF同时处理时，诱导的IRAP mRNA水平是相加的，这表明细胞因子增加IRAP mRNA水平的作用方式不同。用IL-4和GM-CSF同时处理的细胞中IL-1 mRNA水平处于中间值。地塞米松和环己酰亚胺抑制所有mRNA的增加，并且不能逆转IL-4诱导的IL-1 mRNA的降低。这些研究确定了在所研究的单核细胞中诱导IRAP的两种细胞因子，并部分表征了IL-1及其拮抗剂IRAP的差异调节。
