Shear-induced cyclooxygenase-2 via a JNK2/c-Jun-dependent pathway regulates prostaglandin receptor expression in chondrocytic cells
Shear-induced cyclooxygenase-2 via a JNK2/c-Jun-dependent pathway regulates prostaglandin receptor expression in chondrocytic cells
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DOI：
10.1074/jbc.m301378200
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发表时间：
2003-08-01
影响因子：
4.8
通讯作者：
Konstantopoulos, K
中科院分区：
文献类型：
--
作者：
Abulencia, JP;Gaspard, R;Konstantopoulos, K
使用 cDNA 微阵列与生物信息学工具相结合，我们阐明了调节环氧合酶-2 (COX-2) 的信号级联，COX-2 是一种在风湿性和骨关节炎而非正常软骨中表达的关键促炎酶。 T/C-28a2 软骨细胞暴露于流体剪切会导致 c-Jun N 末端激酶 2 (JNK2)、c-Jun 和 COX-2 的共同调节以及前列腺素受体 EP2 和 EP3a1 的下游表达。 JNK2 转录抑制消除了剪切诱导的 COX-2、EP2 和 EP3a1 mRNA 上调以及 c-Jun 磷酸化。使用反义 c-Jun 寡核苷酸进行的功能性敲除实验表明，剪切诱导的 COX-2、EP2 和 EP3a1 转录物被消除，但 JNK2 转录物未被消除。此外，抑制 COX-2 活性可消除剪切诱导的 EP2 和 EP3a1 mRNA 上调。因此，存在一条生化途径，其中流体剪切通过 JNK2/c-Jun 依赖性途径激活 COX-2，进而引发下游 EP2 和 EP3a1 mRNA 合成。
Using cDNA microarrays coupled with bioinformatics tools, we elucidated a signaling cascade regulating cyclooxygenase-2 (COX-2), a pivotal pro-inflammatory enzyme expressed in rheumatic and osteoarthritic, but not normal, cartilage. Exposure of T/C-28a2 chondrocytic cells to fluid shear results in co-regulation of c-Jun N-terminal kinase2 (JNK2), c-Jun, and COX-2 as well as concomitant downstream expression of prostaglandin receptors EP2 and EP3a1. JNK2 transcript inhibition abrogated shear-induced COX-2, EP2, and EP3a1 mRNA up-regulation as well as c-Jun phosphorylation. Functional knock-out experiments using an antisense c-Jun oligonucleotide revealed the abolition of shear-induced COX-2, EP2, and EP3a1, but not JNK2, transcripts. Moreover, inhibition of COX-2 activity eliminated mRNA upregulation of EP2 and EP3a1 induced by shear. Hence, a biochemical pathway exists wherein fluid shear activates COX-2, via a JNK2/c-Jun-dependent pathway, which in turn elicits downstream EP2 and EP3a1 mRNA synthesis.