IL-15 expression on RA synovial fibroblasts promotes B cell survival.
BACKGROUND
The purpose of this study was to examine the role of RA Synovial Fibroblast (RASFib) IL-15 expression on B cell survival.


METHODS
Magnetically sorted peripheral blood memory B cells from 15 healthy subjects were cocultured with RASFib.


RESULTS
RASFib constitutively expressed membrane IL-15. Survival of isolated B cells cultured for 6 days, below 5%, was extended in coculture with RASFib to 52+/-8% (p<0.001). IL-15 neutralizing agents but not isotype controls, reduced this rate to 31+/-6% (p<0.05). Interestingly, rhIL-15 had no effect on isolated B cells but significantly increased their survival in coculture with RASFib. In parallel, B cell IL-15R chains were upregulated in cocultures. BAFF and VCAM-1, that are expressed on RASFib, were tested as potential candidates involved in upregulating B cell IL-15R. Culture of B cells in the presence of rhBAFF or rhVCAM-1 resulted in significantly increased survival, together with upregulation of all three IL-15R chains; in parallel, rhIL-15 potentiated the anti-apoptotic effect of BAFF and VCAM-1. Both BAFF and VCAM-1 neutralizing agents downmodulated the effect of RASFib on B cell survival and IL-15R expression. In parallel, rhIL-15 had a lower effect on the survival of B cells cocultured with RASFib in the presence of BAFF or VCAM-1 neutralizing agents. Peripheral blood B cells from 15 early RA patients demonstrated an upregulated IL-15R and increased survival in cocultures.


CONCLUSIONS
IL-15 expression on RASFib significantly contributes to the anti-apoptotic effect of RASFib on B cells. IL-15 action is facilitated by BAFF and VCAM-1 expressed on RASFib, through an upregulation of IL-15R chains.
Department of Rheumatology, Hospital Universitario La Paz, Madrid, Spain.
Marta
M
Benito-Miguel
Yolanda
Y
García-Carmona
Alejandro
A
Balsa
María-Belén
MB
Bautista-Caro
Irene
I
Arroyo-Villa
Tatiana
T
Cobo-Ibáñez
María Gema
MG
Bonilla-Hernán
Carlos
C
Pérez de Ayala
Paloma
P
Sánchez-Mateos
Emilio
E
Martín-Mola
María-Eugenia
ME
Miranda-Carús
D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D053264:B-Cell Activating Factor / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007156:Immunologic Memory; D019409:Interleukin-15 / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D053647:Receptors, Interleukin-15 / Q000378:metabolism; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D053264:B-Cell Activating Factor; D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D019010:Vascular Cell Adhesion Molecule-1