Protein kinase Cζ is up-regulated in osteoarthritic cartilage and is required for activation of NF-κB by tumor necrosis factor and interleukin-1 in articular chondrocytes
Protein kinase Cζ is up-regulated in osteoarthritic cartilage and is required for activation of NF-κB by tumor necrosis factor and interleukin-1 in articular chondrocytes
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DOI：
10.1074/jbc.m601905200
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发表时间：
2006-08-25
影响因子：
4.8
通讯作者：
Arai, Maya
中科院分区：
文献类型：
--
作者：
LaVallie, Edward R.;Chockalingam, Priya S.;Arai, Maya
蛋白激酶C zeta（PKC zeta）是一种细胞内丝氨酸/苏氨酸蛋白激酶，其在某些细胞类型中与某些炎性细胞因子（包括白介素-1（IL-1）和肿瘤坏死因子α（TNF-α））的信号传导途径有关。骨关节炎（OA）患者关节软骨细胞中基因表达的研究表明，PKC ζ在人类OA关节软骨临床样本中转录上调。这一发现导致的假设，PKC ζ可能是一个重要的信号成分的精氨酸介导的软骨基质破坏关节软骨细胞，被认为是一个潜在的因素，在OA的病理生理。IL-1处理培养的软骨细胞导致PKC zeta磷酸化迅速增加，暗示PKC zeta激活信号通路。软骨细胞为基础的测定被用来评估PKC zeta活性的NF-κ B B激活和细胞外基质降解介导的IL-1，TNF，或鞘磷脂酶的贡献。在原代软骨细胞中，IL-1和TNF-α引起NF-κ B B活性增加，导致聚集蛋白聚糖酶-1和聚集蛋白聚糖酶-2表达的诱导，随之增加蛋白聚糖降解。这种作用被泛特异性PKC抑制剂RO 31-8220和双吲哚基马来酰亚胺I阻断，被Go 6976部分阻断，并且不受PKC ζ保留抑制剂calphostin C的影响。一种细胞渗透性PKC zeta假底物肽抑制剂能够阻断软骨细胞颗粒培养物中TNF-和IL-1介导的NF-κ B活化和蛋白聚糖降解。此外，显性负性PKC zeta蛋白的过表达有效地阻止了原代软骨细胞中马槟榔碱介导的NF-κ B活化。这些数据暗示PKC ζ作为软骨细胞中IL-1和TNF信号通路的必要组分，其导致骨关节炎软骨中细胞外基质蛋白的分解代谢破坏。
Protein kinase C zeta(PKC zeta) is an intracellular serine/threonine protein kinase that has been implicated in the signaling pathways for certain inflammatory cytokines,including interleukin-1 (IL-1) and tumor necrosis factor alpha(TNF-alpha), in some cell types. A study of gene expression in articular chondrocytes from osteoarthritis (OA) patients revealed that PKC zeta is transcriptionally up-regulated in human OA articular cartilage clinical samples. This finding led to the hypothesis that PKC zeta may be an important signaling component of cytokine-mediated cartilage matrix destruction in articular chondrocytes, believed to be an underlying factor in the pathophysiology of OA. IL-1 treatment of chondrocytes in culture resulted in rapidly increased phosphorylation of PKC zeta, implicating PKC zeta activation in the signaling pathway. Chondrocyte cell-based assays were used to evaluate the contribution of PKC zeta activity in NF-kappa B activation and extracellular matrix degradation mediated by IL-1, TNF, or sphingomyelinase. In primary chondrocytes, IL-1 and TNF-alpha caused an increase in NF-kappa B activity resulting in induction of aggrecanase-1 and aggrecanase-2 expression, with consequent increased proteoglycan degradation. This effect was blocked by the pan-specific PKC inhibitors RO 31-8220 and bisindolylmaleimide I, partially blocked by Go 6976, and was unaffected by the PKC zeta- sparing inhibitor calphostin C. A cell-permeable PKC zeta pseudosubstrate peptide inhibitor was capable of blocking TNF- and IL-1-mediated NF-kappa B activation and proteoglycan degradation in chondrocyte pellet cultures. In addition, overexpression of a dominant negative PKC zeta protein effectively prevented cytokine-mediated NF-kappa B activation in primary chondrocytes. These data implicate PKC zeta as a necessary component of the IL-1 and TNF signaling pathways in chondrocytes that result in catabolic destruction of extracellular matrix proteins in osteoarthritic cartilage.