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

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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.

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Abbreviations

APC:

antigen-presenting cell

ATF-1:

activating transcription factor-1

CIA:

collagen-induced arthritis

CREB:

cAMP response element binding protein

ELISA:

enzyme-linked immunosorbent assay

FCS:

fetal calf serum

IC50:

median inhibitory concentration

IFN:

interferon

IL:

interleukin

LPS:

lipopolysaccharide

M-CSF:

macrophage-colony stimulating factor

NF-κB:

nuclear factor κB

PBMC:

peripheral blood mononuclear cells

PDE:

phosphodiesterase

PKA:

protein kinase A

PKC:

protein kinase C

PMA:

phorbol 12-myristate 13-acetate

RA:

rheumatoid arthritis

RA-SMC:

rheumatoid arthritis synovial membrane cell

RPMI:

Roswell Park Memorial Institute [medium]

Th1/Th2:

T helper cell type 1/2

TNF-α:

tumour necrosis factor α

VIP:

vasoactive intestinal peptide.

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Acknowledgements

This work has been funded by a Wellcome Trust project grant and the Kennedy Institute of Rheumatology is supported by a core grant from the Arthritis and Rheumatism Council of Great Britain.

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Authors and Affiliations

  1. Kennedy Institute of Rheumatology Division, Charing Cross Hospital Campus, Imperial College School of Medicine, 1 Aspenlea Road, Hammersmith, London, W6 8LH, UK

    Andrew D Foey Dr, Sarah Field, Salman Ahmed, Marc Feldmann, Fionula M Brennan & Richard Williams

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

    Abhilash Jain

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  1. Andrew D Foey Dr
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  2. Sarah Field
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  3. Salman Ahmed
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Correspondence to Andrew D Foey Dr.

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Foey, A.D., Field, S., Ahmed, S. et al. Impact of VIP and cAMP on the regulation of TNF-α and IL-10 production: implications for rheumatoid arthritis. Arthritis Res Ther 5, R317 (2003). https://doi.org/10.1186/ar999

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