Tassiulas Ioannis, Park-Min Kyung-Hyun, Hu Yang, Kellerman Lisa, Mevorach Dror, Ivashkiv Lionel B
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York 10021, USA.
Hum Immunol. 2007 Mar;68(3):156-64. doi: 10.1016/j.humimm.2006.12.008. Epub 2007 Jan 8.
Apoptosis is a critical process in tissue homeostasis and results in immediate removal of the dying cell by professional phagocytes such as macrophages and dendritic cells. Phagocytosis of apoptotic cells actively suppresses production of proinflammatory growth factors and cytokines. Impaired phagocytosis of apoptotic cells has been implicated in the pathogenesis of chronic inflammatory and autoimmune diseases. In this study we found that, in addition to suppressing lipopolysaccharide (LPS)-induced production of TNF-alpha and IL-6, phagocytosis of apoptotic cells by macrophages suppressed production of the chemokine CXCL10 that is activated by LPS-induced autocrine-acting type I IFNs. Inhibition of cytokine and chemokine production was not universally affected because LPS-induced production of IL-10 and IL-8 was not significantly affected. Apoptotic cells had minimal effects on LPS-induced activation of NF-kappaB and MAPKs, but induced expression of SOCS proteins and substantially suppressed induction of CXCL10 expression by IFN-alpha. In addition to suppressing LPS responses, apoptotic cells inhibited macrophage responses to another major macrophage activator IFN-gamma by attenuating IFN-gamma-induced STAT1 activation and downstream gene expression. These results identify suppressive effects of apoptotic cells on signal transduction, and extend our understanding of the anti-inflammatory effects of apoptotic cells to include suppression of Jak-STAT signaling.
细胞凋亡是组织稳态中的一个关键过程,它会导致死亡细胞被巨噬细胞和树突状细胞等专职吞噬细胞立即清除。凋亡细胞的吞噬作用能有效抑制促炎生长因子和细胞因子的产生。凋亡细胞吞噬功能受损与慢性炎症和自身免疫性疾病的发病机制有关。在本研究中,我们发现,巨噬细胞对凋亡细胞的吞噬作用除了能抑制脂多糖(LPS)诱导的肿瘤坏死因子-α(TNF-α)和白细胞介素-6(IL-6)的产生外,还能抑制由LPS诱导的自分泌作用的Ⅰ型干扰素激活的趋化因子CXCL10的产生。细胞因子和趋化因子产生的抑制并非普遍受到影响,因为LPS诱导的IL-10和IL-8的产生并未受到显著影响。凋亡细胞对LPS诱导的核因子-κB(NF-κB)和丝裂原活化蛋白激酶(MAPKs)的激活影响极小,但能诱导细胞因子信号转导抑制因子(SOCS)蛋白的表达,并显著抑制干扰素-α(IFN-α)对CXCL10表达的诱导。除了抑制LPS反应外,凋亡细胞还通过减弱干扰素-γ(IFN-γ)诱导的信号转导和转录激活因子1(STAT1)的激活及下游基因表达,抑制巨噬细胞对另一种主要巨噬细胞激活剂IFN-γ的反应。这些结果确定了凋亡细胞对信号转导的抑制作用,并将我们对凋亡细胞抗炎作用的理解扩展到包括对Jak-STAT信号通路的抑制。