Hong Hua, Jang Byeong-Churl
Department of Molecular Medicine, College of Medicine, Keimyung University, Dalseo-gu, Daegu 704-701, Republic of Korea.
Int J Mol Med. 2014 Dec;34(6):1640-6. doi: 10.3892/ijmm.2014.1967. Epub 2014 Oct 14.
Hearing loss can be induced by multiple causes, including cochlear inflammation. Prednisone (PDN) is a well-known steroid clinically used in the treatment of hearing loss. In the present study, we investigated the inhibitory effects and the mechanisms of action of PDN on the expression of cyclooxygenase (COX)-2, an inflammatory enzyme involved in the production of prostaglandins (PGs), in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells (a murine auditory cell line) treated with the inflammatory cytokine, interleukin (IL)-1β. The exposure of HEI-OC1 cells to IL-1β increased COX-2 protein and mRNA expression, COX-2 promoter-driven luciferase activity and COX-2 enzymatic activity [as indicated by the increased production of prostaglandin E2 (PGE2), a major COX-2 metabolite]. However, PDN markedly inhibited the IL-1β-induced COX-2 protein and mRNA expression, COX-2 promoter activity and PGE2 production in the HEI-OC1 cells without affecting COX-2 protein and mRNA stability. PDN further inhibited the IL-1β-induced activation of extracellular signal-regulated kinase (ERK)-1/2 and c-Jun N-terminal kinase (JNK)-1, but had no effect on the cytokine-induced activation of p38 MAPK and proteolysis of IκB-α, a nuclear factor-κB (NF-κB) inhibitory protein. PDN also partially suppressed the IL-1β‑induced activation of activator protein (AP)-1 (but not that of NF-κB) promoter-driven luciferase activity. Of note, the inhibitory effects of PDN on the IL-1β-induced expression of COX-2 and the activation of ERK-1/2 and JNK-1 in the HEI-OC1 cells were significantly diminished by RU486, a glucocorticoid receptor (GR) antagonist, suggesting that PDN exerts its inhibitory effects through GR. To the best of our knowledge, our study demonstrates for the first time that PDN inhibits the IL-1β-induced COX-2 expression and activity in HEI-OC1 cells by COX-2 transcriptional repression, which is partly associated with the inhibition of ERK-1/2, JNK-1 and AP-1 activation.
听力损失可由多种原因引起，包括耳蜗炎症。泼尼松（PDN）是临床上用于治疗听力损失的一种知名类固醇药物。在本研究中，我们研究了PDN对环氧化酶（COX）-2表达的抑制作用及其作用机制，COX-2是一种参与前列腺素（PGs）产生的炎性酶，在经炎性细胞因子白细胞介素（IL）-1β处理的豪斯耳科研究所-柯蒂氏器1（HEI-OC1）细胞（一种小鼠听觉细胞系）中。将HEI-OC1细胞暴露于IL-1β会增加COX-2蛋白和mRNA表达、COX-2启动子驱动的荧光素酶活性以及COX-2酶活性[前列腺素E2（PGE2）产量增加表明，PGE2是COX-2的主要代谢产物]。然而，PDN显著抑制IL-1β诱导的HEI-OC1细胞中COX-2蛋白和mRNA表达、COX-2启动子活性和PGE2产生，而不影响COX-2蛋白和mRNA稳定性。PDN进一步抑制IL-1β诱导的细胞外信号调节激酶（ERK）-1/2和c-Jun氨基末端激酶（JNK）-1的激活，但对细胞因子诱导的p38丝裂原活化蛋白激酶（MAPK）激活和核因子κB（NF-κB）抑制蛋白IκB-α的蛋白水解没有影响。PDN还部分抑制IL-1β诱导的激活蛋白（AP）-1（而非NF-κB）启动子驱动的荧光素酶活性。值得注意的是，糖皮质激素受体（GR）拮抗剂RU486显著减弱了PDN对IL-1β诱导的HEI-OC1细胞中COX-2表达以及ERK-1/2和JNK-1激活的抑制作用，这表明PDN通过GR发挥其抑制作用。据我们所知，我们的研究首次证明，PDN通过COX-2转录抑制来抑制IL-1β诱导的HEI-OC1细胞中COX-2的表达和活性，这部分与抑制ERK-1/2、JNK-1和AP-1激活有关。
