title: 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.
authors: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.
authors: Mohammad
authors: M
authors: Abdel-Halim
authors: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.
authors: Sarah S
authors: SS
authors: Darwish
authors: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.
authors: Ahmed K
authors: AK
authors: ElHady
authors: Pharmaceutical Biology, Saarland University, Saarbrücken, Germany.
authors: Jessica
authors: J
authors: Hoppstädter
authors: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.
authors: Ashraf H
authors: AH
authors: Abadi
authors: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarbrücken, Germany.
authors: Rolf W
authors: RW
authors: Hartmann
authors: Pharmaceutical Biology, Saarland University, Saarbrücken, Germany.
authors: Alexandra K
authors: AK
authors: Kiemer
authors: Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany. Electronic address: ma.engel@mx.uni-saarland.de.
authors: Matthias
authors: M
authors: Engel
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D020298:U937 Cells; D000099221:Protein Kinase C zeta
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D000099221:Protein Kinase C zeta; C000617193:MA130 compound
keywords: COPD; NF-κB; PKC-zeta; Pharmacological target; qPCR array