PMID- 21342916
OWN - NLM
STAT- MEDLINE
DCOM- 20110713
LR  - 20110504
IS  - 1468-2060 (Electronic)
IS  - 0003-4967 (Linking)
VI  - 70
IP  - 6
DP  - 2011 Jun
TI  - Phosphodiesterase 4 (PDE4) regulation of proinflammatory cytokine and chemokine 
      release from rheumatoid synovial membrane.
PG  - 1130-7
LID - 10.1136/ard.2010.134825 [doi]
AB  - BACKGROUND: The cAMP-metabolising enzyme, phosphodiesterase 4 (PDE4), has been 
      implicated in a number of immune responses, including tumour necrosis factor alpha 
      (TNFalpha) 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 TNFalpha 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)-1alpha, MIP-1beta (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 1beta 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. CONCLUSION: 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.
FAU - Crilly, Anne
AU  - Crilly A
AD  - Institute of Infection, Immunity and Infl ammation, Glasgow Biomedical Research 
      Centre, University of Glasgow, Glasgow, UK. anne.crilly@glasgow.ac.uk
FAU - Robertson, Susan E
AU  - Robertson SE
FAU - Reilly, James H
AU  - Reilly JH
FAU - Gracie, J Alastair
AU  - Gracie JA
FAU - Lai, Wen-Qi
AU  - Lai WQ
FAU - Leung, Bernard P
AU  - Leung BP
FAU - Life, Paul F
AU  - Life PF
FAU - McInnes, Iain B
AU  - McInnes IB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110221
PL  - England
TA  - Ann Rheum Dis
JT  - Annals of the rheumatic diseases
JID - 0372355
RN  - 0 (Cytokines)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Phosphodiesterase 4 Inhibitors)
RN  - 0 (RNA, Small Interfering)
RN  - EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4)
SB  - IM
MH  - Arthritis, Rheumatoid/enzymology/*immunology/pathology
MH  - Cell Communication/immunology
MH  - Cells, Cultured
MH  - Coculture Techniques
MH  - Cyclic Nucleotide Phosphodiesterases, Type 4/genetics/*physiology
MH  - Cytokines/biosynthesis/*metabolism
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation/drug effects
MH  - Humans
MH  - Inflammation Mediators/*metabolism
MH  - Phosphodiesterase 4 Inhibitors/pharmacology
MH  - RNA, Small Interfering/genetics
MH  - Synovial Membrane/drug effects/enzymology/*immunology
MH  - Synovitis/enzymology/immunology
MH  - T-Lymphocytes/drug effects/immunology
EDAT- 2011/02/24 06:00
MHDA- 2011/07/14 06:00
CRDT- 2011/02/24 06:00
PHST- 2011/02/24 06:00 [entrez]
PHST- 2011/02/24 06:00 [pubmed]
PHST- 2011/07/14 06:00 [medline]
AID - ard.2010.134825 [pii]
AID - 10.1136/ard.2010.134825 [doi]
PST - ppublish
SO  - Ann Rheum Dis. 2011 Jun;70(6):1130-7. doi: 10.1136/ard.2010.134825. Epub 2011 Feb 
      21.