Rheumatoid Arthritis Basic Science Studies
http://www3.interscience.wiley.com/journal/117949635/ab...ct?CRETRY=1&SRETRY=0

Genetic association of vasoactive intestinal peptide receptor with rheumatoid arthritis: Altered expression and signal in immune cells

Mario Delgado 1 *, Gema Robledo 1, Blanca Rueda 1, Nieves Varela 1, Francisco O'Valle 2, Pedro Hernandez-Cortes 3, Marta Caro 1, Gisela Orozco 1, Elena Gonzalez-Rey 4, Javier Martin 1
1Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain
2University of Granada, Granada, Spain
3San Cecilio University Hospital, Granada, Spain
4University of Seville, Seville, Spain

email: Mario Delgado (mdelgado@ipb.csic.es)

*Correspondence to Mario Delgado, Instituto de Parasitologia y Biomedicina, CSIC, Avenida del Conocimiento s/n, PT Ciencias de la Salud, Granada 18100, Spain

Funded by:
Junta de Andalucía (Proyectos de Excelencia, CTS-870)
Plan Nacional de I+D; Grant Number: SAF06-00398

Abstract

Objective
Vasoactive intestinal peptide (VIP) has been shown to be one of the endogenous factors involved in the maintenance of immune tolerance. Administration of VIP ameliorates clinical signs in various experimental autoimmune disorders. This study was undertaken to investigate whether the exacerbated inflammatory autoimmune response in rheumatoid arthritis (RA) might result directly from altered expression and/or signaling of VIP receptors in immune cells.

Methods
The effect of specific agonists of different VIP receptors on collagen-induced arthritis in mice was investigated by clinical and histologic assessment and measurement of cytokine and chemokine production. Expression of VIP receptor type 1 (VPAC1) in synovial cells and monocytes from RA patients was determined by flow cytometry. Potential associations of VPAC1 genetic polymorphisms with RA susceptibility were investigated.

Results
A VPAC1 agonist was very efficient in the treatment of experimental arthritis, and deficient expression of VPAC1 in immune cells of RA patients was associated with the predominant proinflammatory Th1 milieu found in this disease. Immune cells derived from RA patients were less responsive to VIP signaling than were cells from healthy individuals and showed reduced VIP-mediated immunosuppressive activity, rendering leukocytes and synovial cells more proinflammatory in RA. A significant association between multiple-marker haplotypes of VPAC1 and susceptibility to RA was found, suggesting that the reduced VPAC1 expression in RA-derived immune cells is associated with the described VPAC1 genetic polymorphism.

Conclusion
These findings are highly relevant to the understanding of RA pathogenesis. They suggest that VIP signaling through VPAC1 is critical to maintaining immune tolerance in RA. In addition, the results indicate that VPAC1 may be a novel therapeutic target in RA.



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Received: 28 August 2007; Accepted: 7 December 2007
Digital Object Identifier (DOI)