Neutralizing IL-21 and IL-15 inhibits pro-inflammatory cytokine production in rheumatoid arthritis.
Interleukin IL-21 and IL-15 belong to the common gamma-chain receptor family. IL-15 represents a novel therapeutic target in rheumatoid arthritis (RA), whereas less is known about the role of IL-21 in human inflammatory diseases. We have analysed the effects of blocking IL-21 and IL-15 on spontaneous production of pro-inflammatory cytokines in RA synovial cell cultures. RA synovial membrane cells were cultured in the presence of an IL-21R-Fc chimera or a neutralizing IL-15 antibody and production of tumour necrosis factor (TNF)alpha, IL-6 and IL-1beta was measured by enzyme-linked immunosorbent assay (ELISA). Expression of IL-21 and IL-15 in RA synovium was measured by RT-PCR and ELISA. mRNA for IL-21 and IL-21R was detected in the culture cell lysates. Protein for IL-15 was found at detectable levels in the cell lysates. Both the IL-21R-Fc chimera and anti-IL-15 antibody inhibited cytokine release, although substantially more IL-21R-Fc was needed. IL-21R-Fc at the highest dose (100 microg/ml) significantly reduced TNFalpha production by 50%, IL-6 by 57% and IL-1beta by 81%. Anti-IL-15 antibody (5 microg/ml) significantly inhibited TNFalpha release by 51%, IL-6 by 37% and IL-1beta by 82% in line with previous published observations. The data confirm that IL-15 plays a role in RA and suggests that IL-21 is also involved in driving the pro-inflammatory cytokine response in RA.
Andersson
A K
AK
Kennedy Institute of Rheumatology Division, Imperial College Faculty of Medicine, London, UK.
Feldmann
M
M
Brennan
F M
FM
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology; D019409:Interleukin-15 / Q000037:antagonists & inhibitors / Q000276:immunology*; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000166:cytology / Q000276:immunology; D000098546:Interleukin-21
D016207:Cytokines; D018836:Inflammation Mediators; D019409:Interleukin-15; D007378:Interleukins; D000098546:Interleukin-21