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

Abstract 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.