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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 alpha (TNF-alpha) with no effect on IL-10, whereas VIP fails to regulate IL-10 and TNF-alpha 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-alpha production and modulated T-cell response by inhibiting TNF-alpha and IFN-gamma. VIP's lack of effect on IL-10 and its slight effect on TNF-alpha 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-alpha, 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.

Original publication

DOI

10.1186/ar999

Type

Journal article

Journal

Arthritis Res Ther

Publication Date

2003

Volume

5

Pages

R317 - R328

Keywords

3',5'-Cyclic-AMP Phosphodiesterases, Arthritis, Rheumatoid, Bucladesine, Cells, Cultured, Colforsin, Cyclic AMP, Cyclic AMP-Dependent Protein Kinase Type II, Cyclic AMP-Dependent Protein Kinases, Cyclic Nucleotide Phosphodiesterases, Type 4, Gene Expression Regulation, Humans, Interferon-gamma, Interleukin-10, Ionomycin, Lipopolysaccharides, Macrophages, Monocytes, Phosphodiesterase Inhibitors, Protein Kinase C, Rolipram, Synovial Membrane, T-Lymphocytes, Tetradecanoylphorbol Acetate, Tumor Necrosis Factor-alpha, Vasoactive Intestinal Peptide