Stein Erica V, Miller Thomas W, Ivins-O'Keefe Kelly, Kaur Sukhbir, Roberts David D
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1500, USA.
Microbiology and Immunology Program of the Institute for Biomedical Sciences, Departments of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC, 20037, USA.
Sci Rep. 2016 Jan 27;6:19684. doi: 10.1038/srep19684.
Thrombospondin-1 regulates inflammation by engaging several cell surface receptors and by modulating activities of other secreted factors. We have uncovered a novel role of thrombospondin-1 in modulating production and activation of the proinflammatory cytokine IL-1β by human and murine macrophages. Physiological concentrations of thrombospondin-1 limit the induction by lipopolysaccharide of IL-1β mRNA and total protein production by human macrophages. This inhibition can be explained by the ability of thrombospondin-1 to disrupt the interaction between CD47 and CD14, thereby limiting activation of NFκB/AP-1 by lipopolysaccharide. Only the CD47-binding domain of thrombospondin-1 exhibits this activity. In contrast, CD47, CD36, and integrin-binding domains of thrombospondin-1 independently enhance the inflammasome-dependent maturation of IL-1β in human THP-1 monocyte-derived macrophages. Correspondingly, mouse bone marrow-derived macrophages that lack either thrombospondin-1 or CD47 exhibit diminished induction of mature IL-1β in response to lipopolysaccharide. Lack of CD47 also limits lipopolysaccharide induction of IL-1β, NLRP3, and caspase-1 mRNAs. These data demonstrate that thrombospondin-1 exerts CD47-dependent and -independent pro-and anti-inflammatory effects on the IL-1β pathway. Therefore, thrombospondin-1 and its receptor CD47 may be useful targets for limiting the pro-inflammatory effects of lipopolysaccharide and for treating endotoxemia.
血小板反应蛋白-1通过与多种细胞表面受体结合并调节其他分泌因子的活性来调控炎症反应。我们发现了血小板反应蛋白-1在调节人和小鼠巨噬细胞促炎细胞因子IL-1β的产生和激活方面的新作用。生理浓度的血小板反应蛋白-1可限制脂多糖诱导人巨噬细胞产生IL-1β mRNA和总蛋白。这种抑制作用可以通过血小板反应蛋白-1破坏CD47与CD14之间相互作用的能力来解释，从而限制脂多糖对NFκB/AP-1的激活。只有血小板反应蛋白-1的CD47结合结构域具有这种活性。相反，血小板反应蛋白-1的CD47、CD36和整合素结合结构域可独立增强人THP-1单核细胞衍生巨噬细胞中炎性小体依赖性的IL-1β成熟。相应地，缺乏血小板反应蛋白-1或CD47的小鼠骨髓来源巨噬细胞对脂多糖的反应中成熟IL-1β的诱导减少。缺乏CD47也会限制脂多糖对IL-1β、NLRP3和caspase-1 mRNA的诱导。这些数据表明，血小板反应蛋白-1对IL-1β途径发挥CD47依赖性和非依赖性的促炎和抗炎作用。因此，血小板反应蛋白-1及其受体CD47可能是限制脂多糖促炎作用和治疗内毒素血症的有用靶点。
