Phosphodiesterase 4 (PDE4) regulation of proinflammatory cytokine and chemokine release from rheumatoid synovial membrane

Crilly, A., Robertson, S.E., Reilly, J.H., Gracie, J.A., Lai, W.-Q., Leung, B.P., Life, P.F. and McInnes, I.B. (2011) Phosphodiesterase 4 (PDE4) regulation of proinflammatory cytokine and chemokine release from rheumatoid synovial membrane. Annals of the Rheumatic Diseases, 70(6), pp. 1130-1137. (doi:10.1136/ard.2010.134825) (PMID:21342916)

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Abstract

Background: The cAMP-metabolising enzyme, phosphodiesterase 4 (PDE4), has been implicated in a number of immune responses, including tumour necrosis factor alpha (TNF alpha) 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 TNF alpha 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)-1 alpha, MIP-1 beta (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 1 beta 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Crilly, Dr Anne and Reilly, Mr James and Leung, Dr Bernard and Gracie, Professor J Alastair
Authors: Crilly, A., Robertson, S.E., Reilly, J.H., Gracie, J.A., Lai, W.-Q., Leung, B.P., Life, P.F., and McInnes, I.B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Annals of the Rheumatic Diseases
Publisher:BMJ Publishing Group
ISSN:0003-4967
ISSN (Online):1468-2060
Published Online:21 February 2011

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