Lactic acid inhibits iNKT cell functions via a phosphodiesterase-5 dependent pathway
Lactic acid inhibits iNKT cell functions via a phosphodiesterase-5 dependent pathway
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乳酸通过磷酸二酯酶 5 依赖性途径抑制 iNKT 细胞功能
DOI：
10.1016/j.bbrc.2021.02.012
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发表时间：
2021
影响因子：
3.1
通讯作者：
Bai Li
中科院分区：
文献类型：
--
作者：
Wang Lili;Wu Qielan;Liu Jiwei;Zhang Huimin;Bai Li
肿瘤微环境中的乳酸抑制iNKT细胞的功能，从而抑制其抗肿瘤作用。其潜在机制仍不清楚。在这里，我们发现，磷酸二酯酶-5抑制剂，西地那非和他达拉非，以cGMP-γ途径依赖的方式促进iNKT细胞干扰素-PKG和IL-4的产生。为了有利于细胞因子的产生，iNKT细胞在激活后降低了Pde5amRNA水平。与乳酸引起的细胞因子减少相一致，乳酸提高了激活的iNKT细胞中Pde5amRNA的水平。结果，磷酸二酯酶-5抑制剂部分恢复了乳酸处理细胞中细胞因子的产生。我们的结果表明，磷酸二酯酶-5抑制了iNKT细胞中细胞因子的产生，这是乳酸导致iNKT细胞功能障碍的原因之一。
Lactic acid in tumor microenvironment inhibits iNKT cell functions and thus dampens their anti-tumor efficacy. The underlying mechanisms remain unclear. Here, we show that phosphodiesterase-5 inhibitors, sildenafil and tadalafil, promote IFN-γ and IL-4 production in iNKT cells in a cGMP-PKG pathway dependent manner. To favor their cytokine production, iNKT cells reducePde5amRNA lever after activation. In line with the reduction of cytokines caused by lactic acid, lactic acid elevatesPde5amRNA lever in activated iNKT cells. As a result, phosphodiesterase-5 inhibitor partially restores the cytokine production in lactic acid-treated cells. Our results demonstrate that phosphodiesterase-5 inhibits cytokine production in iNKT cells, and that contributes to the lactic acid-caused dysfunction of iNKT cells.