Nair Sunitha, Arora Suruchi, Lim Jyue Yuan, Lee Lay Hoon, Lim Lina H K
Department of Physiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 28 Medical Drive, Singapore, 117456, Singapore.
Cell Stress Chaperones. 2015 Jul;20(4):583-93. doi: 10.1007/s12192-015-0580-5. Epub 2015 Mar 10.
Febrile temperatures can induce stress responses which protect cells from damage and can reduce inflammation during infections and sepsis. However, the mechanisms behind the protective functions of heat in response to the bacterial endotoxin LPS are unclear. We have recently shown that Annexin-1 (ANXA1)-deficient macrophages exhibited higher TNFα levels after LPS stimulation. Moreover, we have previously reported that ANXA1 can function as a stress protein. Therefore in this study, we determined if ANXA1 is involved in the protective effects of heat on cytokine levels in macrophages after heat and LPS. Exposure of macrophages to 42 °C for 1 h prior to LPS results in an inhibition of TNFα production, which was not evident in ANXA1(-/-) macrophages. We show that this regulation involves primarily MYD88-independent pathways. ANXA1 regulates TNFα mRNA stability after heat and LPS, and this is dependent on endogenous ANXA1 expression and not exogenously secreted factors. Further mechanistic studies revealed the possible involvement of the heat shock protein HSP70 and JNK in the heat and inflammatory stress response regulated by ANXA1. This study shows that ANXA1, an immunomodulatory protein, is critical in the heat stress response induced after heat and endotoxin stimulation.
发热温度可引发应激反应，这种反应能保护细胞免受损伤，并可在感染和脓毒症期间减轻炎症。然而，热针对细菌内毒素脂多糖（LPS）的保护功能背后的机制尚不清楚。我们最近发现，缺乏膜联蛋白-1（ANXA1）的巨噬细胞在LPS刺激后表现出更高的肿瘤坏死因子α（TNFα）水平。此外，我们之前报道过ANXA1可作为一种应激蛋白发挥作用。因此，在本研究中，我们确定了ANXA1是否参与热对热刺激和LPS刺激后巨噬细胞中细胞因子水平的保护作用。在LPS刺激前将巨噬细胞暴露于42℃ 1小时会导致TNFα产生受到抑制，这在ANXA1基因敲除（ANXA1(-/-)）的巨噬细胞中并不明显。我们发现这种调节主要涉及不依赖髓样分化因子88（MYD88）的信号通路。ANXA1在热刺激和LPS刺激后调节TNFα mRNA的稳定性，这依赖于内源性ANXA1的表达，而非外源性分泌因子。进一步的机制研究揭示了热休克蛋白HSP70和应激活化蛋白激酶（JNK）可能参与了由ANXA1调节的热应激和炎症应激反应。本研究表明，免疫调节蛋白ANXA1在热刺激和内毒素刺激后诱导的热应激反应中起关键作用。
