title: Phosphodiesterase 4 (PDE4) regulation of proinflammatory cytokine and chemokine release from rheumatoid synovial membrane.
abstract: BACKGROUND
  The cAMP-metabolising enzyme, phosphodiesterase 4 (PDE4), has been implicated in a number of immune responses, including tumour necrosis factor α (TNFα) production. To date, few data have directly addressed whether synovial cytokine and chemokine production is modified by PDE4.
  
  
  OBJECTIVE
  Using specific PDE4 inhibitors, roflumilast plus two novel inhibitors, INH 0061 and INH 0062, the authors studied the effect of PDE4 inhibition on proinflammatory cytokine and chemokine release from primary rheumatoid arthritis (RA) synovial digest suspensions and in a macrophage T cell co-culture assay system.
  
  
  RESULTS
  All PDE4 inhibitors dose-dependently reduced the release of TNFα from primary synovial membrane cultures (n=5), half maximal inhibitory concentration (IC(50)) 300-30 nM, p<0.05. Similarly, a significant suppression in the release the proinflammatory chemokines, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1α, MIP-1β (IC(50) 300-30 nM) and regulated upon activation normal T-cell expressed and secreted (RANTES) (IC(50) 3 nM) was also observed, p<0.05. While interleukin 1β was also reduced, it did not achieve an IC(50). These observations were further confirmed in a macrophage T cell co-culture system, demonstrating the importance of PDE4 pathways in regulating cytokine/chemokine release in a cellular interaction implicated in inflammatory synovitis. Subsequent studies using the human monocytic cell line U937 also demonstrated cytokine regulation with PDE4 knockdown utilising a small interfering RNA approach.
  
  
  CONCLUSIONS
  These data provide direct evidence of PDE4-dependent pathways in human RA synovial inflammatory cytokine and chemokine release and may provide a novel approach in treating chronic autoimmune conditions such as RA.
authors.affiliation: Institute of Infection, Immunity and Infl ammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, UK. anne.crilly@glasgow.ac.uk
authors.forename: Anne
authors.initials: A
authors.lastname: Crilly
authors.forename: Susan E
authors.initials: SE
authors.lastname: Robertson
authors.forename: James H
authors.initials: JH
authors.lastname: Reilly
authors.forename: J Alastair
authors.initials: JA
authors.lastname: Gracie
authors.forename: Wen-Qi
authors.initials: WQ
authors.lastname: Lai
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Leung
authors.forename: Paul F
authors.initials: PF
authors.lastname: Life
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
mesh_terms: D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D013583:Synovial Membrane / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D013585:Synovitis / Q000201:enzymology / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D058988:Phosphodiesterase 4 Inhibitors; D034741:RNA, Small Interfering; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4