Herrero Carmen, Hu Xiaoyu, Li Wai Ping, Samuels Stuart, Sharif M Nusrat, Kotenko Sergei, Ivashkiv Lionel B
Department of Medicine, Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
J Immunol. 2003 Nov 15;171(10):5034-41. doi: 10.4049/jimmunol.171.10.5034.
One important mechanism of cross-regulation by opposing cytokines is inhibition of signal transduction, including inhibition of Janus kinase-STAT signaling by suppressors of cytokine signaling. We investigated whether IFN-gamma, a major activator of macrophages, inhibited the activity of IL-10, an important deactivator. Preactivation of macrophages with IFN-gamma inhibited two key anti-inflammatory functions of IL-10, the suppression of cytokine production and of MHC class II expression. Gene expression profiling showed that IFN-gamma broadly suppressed the ability of IL-10 to induce or repress gene expression. Although IFN-gamma induced expression of suppressor of cytokine signaling proteins, IL-10 signal transduction was not suppressed and IL-10 activation of Janus kinases and Stat3 was preserved. Instead, IFN-gamma switched the balance of IL-10 STAT activation from Stat3 to Stat1, with concomitant activation of inflammatory gene expression. IL-10 activation of Stat1 required the simultaneous presence of IFN-gamma. These results demonstrate that IFN-gamma operates a switch that rapidly regulates STAT activation by IL-10 and alters macrophage responses to IL-10. Dynamic regulation of the activation of different STATs by the same cytokine provides a mechanism by which cells can integrate and balance signals delivered by opposing cytokines, and extends our understanding of cross-regulation by opposing cytokines to include reprogramming of signaling and alteration of function.
细胞因子相互拮抗的交叉调节的一个重要机制是抑制信号转导，包括细胞因子信号转导抑制因子对Janus激酶-信号转导子和转录激活子（JAK-STAT）信号通路的抑制。我们研究了巨噬细胞的主要激活因子γ干扰素（IFN-γ）是否会抑制重要的失活因子白细胞介素10（IL-10）的活性。用IFN-γ预激活巨噬细胞会抑制IL-10的两项关键抗炎功能，即细胞因子产生的抑制以及主要组织相容性复合体II类分子（MHC II）表达的抑制。基因表达谱分析显示，IFN-γ广泛抑制IL-10诱导或抑制基因表达的能力。尽管IFN-γ诱导了细胞因子信号转导抑制蛋白的表达，但IL-10信号转导未受抑制，Janus激酶和Stat3的IL-10激活作用得以保留。相反，IFN-γ将IL-10 STAT激活的平衡从Stat3转换为Stat1，同时激活炎症基因表达。IL-10对Stat1的激活需要IFN-γ同时存在。这些结果表明，IFN-γ发挥了一个开关的作用，可快速调节IL-10介导的STAT激活，并改变巨噬细胞对IL-10的反应。同一细胞因子对不同STAT激活的动态调节提供了一种机制，通过该机制细胞可以整合并平衡由相互拮抗的细胞因子传递的信号，并将我们对细胞因子相互拮抗的交叉调节的理解扩展到包括信号重编程和功能改变。
