Musso T, Espinoza-Delgado I, Pulkki K, Gusella G L, Longo D L, Varesio L
Biological Carcinogenesis and Development Program, PRI/DynCorp, Frederick, MD.
J Immunol. 1992 Feb 1;148(3):795-800.
IL-2 is a potent activator of effector and secretory activities of human monocytes. Since monocytes are an important source of IL-6, we investigated whether IL-2 can induce IL-6 production and whether regulatory circuits can modulate this process. We found that stimulation of monocytes with IL-2 induced expression of IL-6 mRNA and bioactivity in a dose-dependent manner. Production of IL-6 in monocytes can be induced by other cytokines such as IL-1 beta. By using mAb alpha-IL-1 beta we showed that IL-2-induced IL-6 production is not mediated by the autocrine stimulation of IL-1 beta elicited by IL-2. IL-6 induction by monocytes is not a common response to activating signals because IFN-gamma did not induce IL-6 expression under conditions in which it elicits tumoricidal activity. In contrast, IFN-gamma could completely abrogate the induction of IL-6 expression by IL-1 beta but did not affect the levels of mRNA and the secretion of IL-2-elicited IL-6. We have previously reported that transforming growth factor-beta inhibits IL-6 production in response to IL-1 beta. Studies on the inhibitory activity of transforming growth factor-beta demonstrated that this cytokine differs from IFN-gamma because it inhibited both IL-1- and IL-2-induced IL-6 expression. These data demonstrate that, in human monocytes, both IL-1 and IL-2 stimulate IL-6 expression by independent mechanisms that can be dissociated by the susceptibility to the inhibitory effect of IFN-gamma. IL-6 production is also down-regulated by TGF-beta, whose inhibitory activity is stimulus-unrelated.
白细胞介素-2是人类单核细胞效应和分泌活动的强效激活剂。由于单核细胞是白细胞介素-6的重要来源，我们研究了白细胞介素-2是否能诱导白细胞介素-6的产生，以及调节回路是否能调节这一过程。我们发现，用白细胞介素-2刺激单核细胞能以剂量依赖的方式诱导白细胞介素-6信使核糖核酸的表达和生物活性。单核细胞中白细胞介素-6的产生可由其他细胞因子如白细胞介素-1β诱导。通过使用抗白细胞介素-1β单克隆抗体，我们表明白细胞介素-2诱导的白细胞介素-6产生不是由白细胞介素-2引发的白细胞介素-1β的自分泌刺激介导的。单核细胞对白细胞介素-6的诱导不是对激活信号的常见反应，因为在干扰素-γ引发杀肿瘤活性的条件下，它不会诱导白细胞介素-6的表达。相反，干扰素-γ可以完全消除白细胞介素-1β对白细胞介素-6表达的诱导，但不影响信使核糖核酸的水平和白细胞介素-2引发的白细胞介素-6的分泌。我们之前曾报道，转化生长因子-β可抑制对白细胞介素-1β的反应中白细胞介素-6的产生。对转化生长因子-β抑制活性的研究表明，这种细胞因子与干扰素-γ不同，因为它能抑制白细胞介素-1和白细胞介素-2诱导的白细胞介素-6表达。这些数据表明，在人类单核细胞中，白细胞介素-1和白细胞介素-2通过独立的机制刺激白细胞介素-6的表达，而这两种机制可因对干扰素-γ抑制作用的敏感性不同而区分开来。白细胞介素-6的产生也受到转化生长因子-β的下调，其抑制活性与刺激无关。
