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

Publication date: 10 October 2016
Source:European Journal of Pharmaceutical Sciences, Volume 93
Author(s): Mohammad Abdel-Halim, Sarah S. Darwish, Ahmed K. ElHady, Jessica Hoppstädter, Ashraf H. Abadi, Rolf W. Hartmann, Alexandra K. Kiemer, Matthias Engel
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.

Graphical abstract

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