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Open Access Research article

Impact of VIP and cAMP on the regulation of TNF-α and IL-10 production: implications for rheumatoid arthritis

Andrew D Foey1*, Sarah Field1, Salman Ahmed1, Abhilash Jain2, Marc Feldmann1, Fionula M Brennan1 and Richard Williams1

Author Affiliations

1 Kennedy Institute of Rheumatology Division, Charing Cross Hospital Campus, Imperial College School of Medicine, London, UK

2 Department of Musculoskeletal Surgery, Charing Cross Hospital Campus, Imperial College School of Medicine, London, UK

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Arthritis Res Ther 2003, 5:R317-R328  doi:10.1186/ar999

Published: 3 September 2003

Abstract

Vasoactive intestinal peptide (VIP) is an anti-inflammatory immunomodulatory neuropeptide with therapeutic potential demonstrated for collagen-induced arthritis. The aim of this study was to characterise its potential anti-arthritic effect on human monocytes, macrophages, T cells, and rheumatoid arthritis synovial membrane cells. Monocytes, macrophages, and T cells derived from human peripheral blood were treated with VIP and compared with other cAMP-elevating drugs for a range of activating stimuli. Cytokine production was assessed for cell cultures and, in addition, the ability of VIPs to activate cAMP response element binding protein. VIP partially suppressed monocyte- and macrophage-derived tumour necrosis factor α (TNF-α) with no effect on IL-10, whereas VIP fails to regulate IL-10 and TNF-α production by T lymphocytes. No such modulation of cytokine profile was observed for rheumatoid arthritis synovial membrane cells. Elevation of intracellular cAMP, on the other hand, potently suppressed macrophage TNF-α production and modulated T-cell response by inhibiting TNF-α and IFN-γ. VIP's lack of effect on IL-10 and its slight effect on TNF-α results from cAMP being rapidly degraded as the phosphodiesterase IV inhibitor, rolipram, rescues cAMP-dependent activation of cAMP response element binding protein. Interestingly, macrophages stimulated with phorbol 12-myristate 13-acetate/ionomycin displayed an augmented IL-10 response upon addition of dibutyryl cAMP, with corresponding downregulation in TNF-α, suggesting a complex interaction between protein kinase C and protein kinase A in cytokine regulation. In conclusion, VIP may represent an efficaceous anti-arthritic treatment modulating macrophage and T-cell cytokine profiles when used alongside a phosphodiesterase inhibitor.

Keywords:
IL-10; macrophage; T cells; TNF-α; VIP