Na Yi Rang, Yoon Yi Na, Son Dain, Jung Daun, Gu Gyo Jeong, Seok Seung Hyeok
Macrophage Lab, Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, South Korea.
PLoS One. 2015 Feb 13;10(2):e0118203. doi: 10.1371/journal.pone.0118203. eCollection 2015.
Macrophages play important roles in defense against infection, as well as in homeostasis maintenance. Thus alterations of macrophage function can have unexpected pathological results. Cyclooxygenase (COX) inhibitors are widely used to relieve pain, but the effects of long-term usage on macrophage function remain to be elucidated. Using bone marrow-derived macrophage culture and long-term COX inhibitor treatments in BALB/c mice and zebrafish, we showed that chronic COX inhibition drives macrophages into an inflammatory state. Macrophages differentiated in the presence of SC-560 (COX-1 inhibitor), NS-398 (COX-2 inhibitor) or indomethacin (COX-1/2 inhibitor) for 7 days produced more TNFα or IL-12p70 with enhanced p65/IκB phosphoylation. YmI and IRF4 expression was reduced significantly, indicative of a more inflammatory phenotype. We further observed that indomethacin or NS-398 delivery accelerated zebrafish death rates during LPS induced sepsis. When COX inhibitors were released over 30 days from an osmotic pump implant in mice, macrophages from peritoneal cavities and adipose tissue produced more TNFα in both the basal state and under LPS stimulation. Consequently, indomethacin-exposed mice showed accelerated systemic inflammation after LPS injection. Our findings suggest that macrophages exhibit a more inflammatory phenotype when COX activities are chronically inhibited.
巨噬细胞在抵御感染以及维持体内平衡方面发挥着重要作用。因此，巨噬细胞功能的改变可能会产生意想不到的病理结果。环氧化酶（COX）抑制剂被广泛用于缓解疼痛，但长期使用对巨噬细胞功能的影响仍有待阐明。通过在BALB/c小鼠和斑马鱼中使用骨髓来源的巨噬细胞培养和长期COX抑制剂处理，我们发现慢性COX抑制会使巨噬细胞进入炎症状态。在SC-560（COX-1抑制剂）、NS-398（COX-2抑制剂）或吲哚美辛（COX-1/2抑制剂）存在下分化7天的巨噬细胞产生更多的TNFα或IL-12p70，同时p65/IκB磷酸化增强。Ym1和IRF4表达显著降低，表明其具有更明显的炎症表型。我们进一步观察到，在脂多糖诱导的败血症期间，给予吲哚美辛或NS-398会加速斑马鱼的死亡率。当COX抑制剂通过植入小鼠体内的渗透泵在30天内持续释放时，来自腹腔和脂肪组织的巨噬细胞在基础状态和脂多糖刺激下均产生更多的TNFα。因此，给予吲哚美辛的小鼠在注射脂多糖后全身炎症加速。我们的研究结果表明，当COX活性受到慢性抑制时，巨噬细胞会表现出更明显的炎症表型。
