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


CONCLUSIONS
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.
Delgado
Mario
M
Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain. mdelgado@ipb.csic.es
Robledo
Gema
G
Rueda
Blanca
B
Varela
Nieves
N
O'Valle
Francisco
F
Hernandez-Cortes
Pedro
P
Caro
Marta
M
Orozco
Gisela
G
Gonzalez-Rey
Elena
E
Martin
Javier
J
D000328:Adult; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000503:physiopathology; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000819:agonists / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000819:agonists / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000276:immunology*
D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C495506:VIPR1 protein, human; C495509:VIPR2 protein, human; C495507:Vipr1 protein, mouse; C495510:Vipr2 protein, mouse; D014660:Vasoactive Intestinal Peptide