Pharmacological inhibition of protein kinase C (PKC)ζ downregulates the expression of cytokines involved in the pathogenesis of chronic obstructive pulmonary disease (COPD)

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• 作者：Mohammad Abdel-Halim^a ; Sarah S. Darwish^a ; Ahmed K. ElHady^a ; Jessica Hoppstä ; dter^c ; Ashraf H. Abadi^a ; Rolf W. Hartmann^b ; Alexandra K. Kiemer^c ; Matthias Engel^d ; ^{ma.engel@mx.uni-saarland.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：NF-κB ; COPD ; PKC-zeta ; Pharmacological target ; qPCR array
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2016
• 出版时间：10 October 2016
• 年：2016
• 卷：93
• 期：Complete
• 页码：405-409
• 全文大小：484 K

文摘

The protein kinase PKCζ is involved in the fine regulation of the NF-κB transcriptional activity and, therefore, represents a potential pharmacological target in inflammatory diseases. We previously developed a selective, allosteric inhibitor (MA130) of PKCζ. Now, we investigated which of the NF-κB–regulated gene expressions are suppressed by MA130 after TNFα-stimulation of the macrophage model cell line U937. The analysis of gene expressions using a qPCR array revealed that many cytokines contributing to the pathogenesis and systemic inflammation in chronic obstructive pulmonary disease (COPD), including CCL2, CCL20, CSF2, CXCL1, CXCL10, IL1B and TNFα, were down-regulated by MA130 but not by a PKCζ–inactive control compound. Thus, we provided the first evidence that PKCζ is a potential target for the treatment of COPD by selective small molecules. MA130 inhibited only a subset of NF-κB–dependent gene expressions, suggesting that targeting PKCζ will be more tolerable than total inhibition of NF-κB activation.