Upregulation of PD-L1 Expression by Prostaglandin E2 and the Enhancement of IFN-γ by Anti-PD-L1 Antibody Combined With a COX-2 Inhibitor in Mycoplasma bovis Infection
Upregulation of PD-L1 Expression by Prostaglandin E2 and the Enhancement of IFN-γ by Anti-PD-L1 Antibody Combined With a COX-2 Inhibitor in Mycoplasma bovis Infection
复制标题
DOI：
10.3389/fvets.2020.00012
复制
发表时间：
2020-02-20
影响因子：
3.2
通讯作者：
Ohashi, Kazuhiko
中科院分区：
文献类型：
--
作者：
Goto, Shinya;Konnai, Satoru;Ohashi, Kazuhiko
由牛支原体引起的牛支原体病可引起牛肺炎和乳房炎。我们先前已经证明程序性死亡1(PD-1)/PD-配体1(PD-L1)通路参与了牛分枝杆菌感染过程中的免疫功能障碍，前列腺素E-2(PGE(2))抑制了免疫反应并上调了PD-L1的表达。在本研究中，我们探讨了PGE(2)在免疫功能紊乱中的作用，以及PGE(2)与PD-1/PD-L1通路在牛分枝杆菌感染中的关系。牛分枝杆菌体外刺激可上调牛外周血单个核细胞(PBMC)PGE(2)和PD-L1的表达，可能是通过Toll样受体2实现的。感染牛外周血中PGE(2)水平显著高于未感染牛。感染牛的PGE(2)水平与PD-L1(+)单核细胞比例呈显著正相关。此外，感染牛的血浆PGE(2)产生与PBMC产生的牛分枝杆菌特异性干扰素(干扰素)-γ呈负相关。这些结果表明，PGE(2)可能是PD-L1表达的诱导剂之一，并可能参与牛分枝杆菌感染时的免疫抑制。在体外，使用抗牛PD-L1抗体和环氧合酶2抑制剂的阻断试验显著上调了牛分枝杆菌特异性的干扰素-伽马反应。我们的研究结果可能有助于开发针对PGE(2)和PD-1/PD-L1途径的牛支原体病新的治疗策略。
Bovine mycoplasmosis caused by Mycoplasma bovis results in pneumonia and mastitis in cattle. We previously demonstrated that the programmed death 1 (PD-1)/PD-ligand 1 (PD-L1) pathway is involved in immune dysfunction during M. bovis infection and that prostaglandin E-2 (PGE(2)) suppressed immune responses and upregulated PD-L1 expression in Johne's disease, a bacterial infection in cattle. In this study, we investigated the role of PGE(2) in immune dysfunction and the relationship between PGE(2) and the PD-1/PD-L1 pathway in M. bovis infection. In vitro stimulation with M. bovis upregulated the expressions of PGE(2) and PD-L1 presumably via Toll-like receptor 2 in bovine peripheral blood mononuclear cells (PBMCs). PGE(2) levels of peripheral blood in infected cattle were significantly increased compared with those in uninfected cattle. Remarkably, plasma PGE(2) levels were positively correlated with the proportions of PD-L1(+) monocytes in M. bovis-infected cattle. Additionally, plasma PGE(2) production in infected cattle was negatively correlated with M. bovis-specific interferon (IFN)-gamma production from PBMCs. These results suggest that PGE(2) could be one of the inducers of PD-L1 expression and could be involved in immunosuppression during M. bovis infection. In vitro blockade assays using anti-bovine PD-L1 antibody and a cyclooxygenase 2 inhibitor significantly upregulated the M. bovis-specific IFN-gamma response. Our study findings might contribute to the development of novel therapeutic strategies for bovine mycoplasmosis that target PGE(2) and the PD-1/PD-L1 pathway.