Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada.
Department of Surgery, University of British Columbia, Vancouver, Canada.
PLoS One. 2020 Apr 2;15(4):e0230427. doi: 10.1371/journal.pone.0230427. eCollection 2020.
Macrophage cells form part of our first line defense against pathogens. Macrophages become activated by microbial products such as lipopolysaccharide (LPS) to produce inflammatory mediators, such as TNFα and other cytokines, which orchestrate the host defense against the pathogen. Once the pathogen has been eradicated, the activated macrophage must be appropriately deactivated or inflammatory diseases result. Interleukin-10 (IL10) is a key anti-inflammatory cytokine which deactivates the activated macrophage. The IL10 receptor (IL10R) signals through the Jak1/Tyk2 tyrosine kinases, STAT3 transcription factor and the SHIP1 inositol phosphatase. However, IL10 has also been described to induce the activation of the cyclic adenosine monophosphate (cAMP) regulated protein kinase A (PKA). We now report that IL10R signalling leads to STAT3/SHIP1 dependent expression of the EP4 receptor for prostaglandin E2 (PGE2). In macrophages, EP4 is a Gαs-protein coupled receptor that stimulates adenylate cyclase (AC) production of cAMP, leading to downstream activation of protein kinase A (PKA) and phosphorylation of the CREB transcription factor. IL10 induction of phospho-CREB and inhibition of LPS-induced phosphorylation of p85 PI3K and p70 S6 kinase required the presence of EP4. These data suggest that IL10R activation of STAT3/SHIP1 enhances EP4 expression, and that it is EP4 which activates cAMP-dependent signalling. The coordination between IL10R and EP4 signalling also provides an explanation for why cAMP elevating agents synergize with IL10 to elicit anti-inflammatory responses.
巨噬细胞是我们抵御病原体的第一道防线的一部分。巨噬细胞被微生物产物（如脂多糖[LPS]）激活，产生炎症介质，如 TNFα 和其他细胞因子，这些炎症介质协调宿主对病原体的防御。一旦病原体被根除，激活的巨噬细胞必须被适当失活，否则会导致炎症性疾病。白细胞介素 10（IL10）是一种关键的抗炎细胞因子，可使激活的巨噬细胞失活。IL10 受体（IL10R）通过 Jak1/Tyk2 酪氨酸激酶、STAT3 转录因子和 SHIP1 肌醇磷酸酶信号传导。然而，IL10 也被描述为诱导环腺苷酸（cAMP）调节蛋白激酶 A（PKA）的激活。我们现在报告，IL10R 信号导致 STAT3/SHIP1 依赖性表达前列腺素 E2（PGE2）的 EP4 受体。在巨噬细胞中，EP4 是一种 Gαs-蛋白偶联受体，它刺激腺苷酸环化酶（AC）产生 cAMP，导致蛋白激酶 A（PKA）的下游激活和 CREB 转录因子的磷酸化。IL10 诱导的 phospho-CREB 和抑制 LPS 诱导的 p85 PI3K 和 p70 S6 激酶的磷酸化需要 EP4 的存在。这些数据表明，IL10R 激活 STAT3/SHIP1 增强了 EP4 的表达，并且正是 EP4 激活了 cAMP 依赖性信号传导。IL10R 和 EP4 信号的协调也解释了为什么 cAMP 升高剂与 IL10 协同作用以引发抗炎反应。
