title: Down-regulation of protein kinase Cδ inhibits inducible nitric oxide synthase expression through IRF1.
abstract: In inflammation, pro-inflammatory cytokines and bacterial products induce the production of high amounts of NO by inducible nitric oxide synthase (iNOS) in inflammatory and tissue cells. NO is an effector molecule in innate immunity, and it also has regulatory and pro-inflammatory/destructive effects in the inflammatory process. Protein kinase Cδ (PKCδ) is an important signaling protein regulating B lymphocyte functions, but less is known about its effects in innate immunity and inflammatory gene expression. In the present study we investigated the role of PKCδ in the regulation of iNOS expression in inflammatory conditions. NO production and iNOS expression were induced by LPS or a combination of cytokines IFNγ, IL-1β, and TNFα. Down-regulation of PKCδ by siRNA and inhibition of PKCδ by rottlerin suppressed NO production and iNOS expression in activated macrophages and fibroblasts. PKCδ directed siRNA and inhibition of PKCδ by rottlerin suppressed also the expression of transcription factor IRF1, possibly through inhibition of STAT1 activation. Accordingly, down-regulation of IRF1 by siRNA reduced iNOS expression in response to inflammatory stimuli. In addition, inhibition of PKCδ showed anti-inflammatory effects in carrageenan induced paw inflammation in mice as did iNOS inhibitor L-NIL. These results suggest that inhibitors of PKCδ have anti-inflammatory effects in disease states complicated by enhanced NO production through iNOS pathway.
authors: The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland.
authors: Tiina
authors: T
authors: Leppänen
authors: Riku
authors: R
authors: Korhonen
authors: Mirka
authors: M
authors: Laavola
authors: Riina
authors: R
authors: Nieminen
authors: Raimo K
authors: RK
authors: Tuominen
authors: Eeva
authors: E
authors: Moilanen
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D015153:Blotting, Western; D002351:Carrageenan; D002460:Cell Line; D015536:Down-Regulation; D004487:Edema / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006614:Hindlimb / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020871:RNA Stability / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D050856:Interferon Regulatory Factor-1; D015850:Interleukin-6; C494258:Irf1 protein, mouse; D008070:Lipopolysaccharides; C090663:N(6)-(1-iminoethyl)lysine; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D002351:Carrageenan; C085746:rottlerin; D052247:Nitric Oxide Synthase Type II; D051745:Protein Kinase C-delta; D008239:Lysine