Zhou Xueyuan, Li Junying, Yang Wenxiu
Department of Biophysics, School of Physics, Nankai University, Tianjin, China; Clinic Service Program, Leidos Biomedical Research Inc., Frederick, MD, USA.
Immunology. 2014 Oct;143(2):287-99. doi: 10.1111/imm.12309.
Prostaglandin E2 (PGE2 ) is an important inducer of inflammation, which is also closely linked to the progress of tumours. In macrophages, PGE2 production is regulated by arachidonic acid release and cyclooxygenase-2 (COX-2) expression. In the present study, we found that COX-2 expression can be achieved by activating Ca(2+) /Calmodulin (CaM)-dependent protein kinase II (CaMKII) and cAMP-response element-binding protein (CREB) in rat peritoneal macrophages. Our results indicated that lipopolysaccharide and PMA could elicit the transient increase of the concentration of intracellular free calcium ions ([Ca(2+) ]i ), which induced activation of CaMKs with the presence of CaM. The subtype of CaMKs, CaMKII, then triggered the activation of CREB, which elevated COX-2 expression and PGE2 production in a chronological order. These results suggested that Ca(2+) /CaM-dependent CaMKII plays an important role in mediating COX-2 expression and PGE2 production by activating CREB in macrophages. The study also provides more useful information to clarify the mechanism of calcium regulation of PGE2 production, which plays an essential role in inflammation and cancers.
前列腺素E2（PGE2）是炎症的重要诱导剂，它也与肿瘤进展密切相关。在巨噬细胞中，PGE2的产生受花生四烯酸释放和环氧合酶-2（COX-2）表达的调节。在本研究中，我们发现通过激活大鼠腹腔巨噬细胞中的钙/钙调蛋白（CaM）依赖性蛋白激酶II（CaMKII）和环磷酸腺苷反应元件结合蛋白（CREB），可实现COX-2的表达。我们的结果表明，脂多糖和佛波酯可引起细胞内游离钙离子（[Ca2+]i）浓度的短暂升高，在有CaM存在的情况下诱导CaMKs的激活。CaMKs的亚型CaMKII随后触发CREB的激活，进而按时间顺序提高COX-2的表达和PGE2的产生。这些结果表明，钙/钙调蛋白依赖性CaMKII在巨噬细胞中通过激活CREB介导COX-2表达和PGE2产生方面发挥重要作用。该研究还为阐明PGE2产生的钙调节机制提供了更多有用信息，PGE2在炎症和癌症中起着至关重要的作用。
