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

The protein kinase PKC zeta is involved in the fine regulation of the NF-kappa B transcriptional activity and, therefore, represents a potential pharmacological target in inflammatory diseases. We previously developed a selective, allosteric inhibitor (MA130) of PKC zeta. Now, we investigated which of the NF-kappa B-regulated gene expressions are suppressed by MA130 after TNF alpha-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 TNF alpha, were down-regulated by MA130 but not by a PKC zeta-inactive control compound. Thus, we provided the first evidence that PKC zeta is a potential target for the treatment of COPD by selective small molecules. MA130 inhibited only a subset of NF-kappa B-dependent gene expressions, suggesting that targeting PKC zeta will be more tolerable than total inhibition of NF-kappa B activation. (C) 2016 Elsevier B.V. All rights reserved.