Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritis.
OBJECTIVE
Interleukin-33 (IL-33; or, IL-1F11) was recently identified as the ligand of the IL-1 family receptor T1/ST2. The aim of this study was to examine IL-33 production in human and mouse joints and to investigate the role of IL-33 and T1/ST2 in experimental arthritis.


METHODS
IL-33 expression was examined in human synovial tissue, rheumatoid arthritis (RA) synovial fibroblasts, and arthritic mouse joints. Mice with collagen-induced arthritis (CIA) were treated with blocking anti-ST2 antibody or control antibody beginning at the onset of disease. Arthritis severity was assessed by clinical and histologic scoring. Draining lymph node (LN) cell responses were examined ex vivo, and joint messenger RNA (mRNA) was used for expression profiling.


RESULTS
IL-33 was highly expressed in human RA synovium. In cultured synovial fibroblasts, IL-33 expression was strongly induced by IL-1beta and/or tumor necrosis factor alpha. Furthermore, IL-33 mRNA was detected in the joints of mice with CIA and increased during the early phase of the disease. Administration of a blocking anti-ST2 antibody at the onset of disease attenuated the severity of CIA and reduced joint destruction. Anti-ST2 antibody treatment was associated with a marked decrease in interferon-gamma production as well as with a more limited reduction in IL-17 production by ex vivo-stimulated draining LN cells. Finally, RANKL mRNA levels in the joint were reduced by anti-ST2 treatment.


CONCLUSIONS
IL-33 is produced locally in inflamed joints, and neutralization of IL-33 signaling has a therapeutic effect on the course of arthritis. These observations suggest that locally produced IL-33 may contribute to the pathogenesis of joint inflammation and destruction.
Palmer
Gaby
G
University Hospital of Geneva, and University of Geneva School of Medicine, Geneva, Switzerland.
Talabot-Ayer
Dominique
D
Lamacchia
Céline
C
Toy
Dean
D
Seemayer
Christian A
CA
Viatte
Sébastien
S
Finckh
Axel
A
Smith
Dirk E
DE
Gabay
Cem
C
D000368:Aged; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D000072179:Interleukin-1 Receptor-Like 1 Protein; D020381:Interleukin-17 / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008875:Middle Aged; D053245:RANK Ligand / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology*; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology*
D000888:Antibodies, Anti-Idiotypic; C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D020381:Interleukin-17; D000067596:Interleukin-33; D007378:Interleukins; D008565:Membrane Proteins; D053245:RANK Ligand; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D007371:Interferon-gamma; D003094:Collagen