Rheumatoid arthritis synovial fibroblasts produce a soluble form of the interleukin-7 receptor in response to pro-inflammatory cytokines.
We previously demonstrated that baseline synovial overexpression of the interleukin-7 receptor α-chain (IL-7R) is associated with poor response to tumour necrosis factor (TNF) blockade in rheumatoid arthritis (RA). We found that IL-7R gene expression is induced in fibroblast-like synovial cells (FLS) by the addition of TNF-α, IL-1β and combinations of TNF-α+ IL-1β or TNF-α+ IL-17, thereby suggesting that these cytokines play a role in the resistance to TNF blockade in RA. Because FLS and CD4 T cells also produce a soluble form of IL-7R (sIL-7R), resulting from an alternative splicing of the full-length transcript, we wondered whether expression of sIL-7R is similarly regulated by pro-inflammatory cytokines. We also investigated whether sIL-7R is detectable in the serum of RA patients and associated with response to TNF blockade. RA FLS were cultured in the presence of pro-inflammatory cytokines and sIL-7R concentrations were measured in culture supernatants. Similarly, sIL-7R titres were measured in sera obtained from healthy individuals, early untreated RA patients with active disease and disease-modifying anti-rheumatic drug (DMARD)-resistant RA patients prior to initiation of TNF-blockade. Baseline serum sIL-7R titres were correlated with validated clinical measurements of disease activity. We found that exposure of RA FLS to pro-inflammatory cytokines (TNF-α, IL-1β and combinations of TNF-α and IL-1β or TNF-α and IL-17) induces sIL-7R secretion. Activated CD4 T cells also produce sIL-7R. sIL-7R serum levels are higher in RA patients as compared to controls. In DMARD-resistant patients, high sIL-7R serum concentrations are strongly associated with poor response to TNF-blockade. In conclusion, sIL-7R is induced by pro-inflammatory cytokines in RA FLS. sIL-7R could qualify as a new biomarker of response to therapy in RA.
Rheumatology Department, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
V
V
Badot
P
P
Durez
B J
BJ
Van den Eynde
A
A
Nzeusseu-Toukap
F A
FA
Houssiau
B R
BR
Lauwerys
D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D013583:Synovial Membrane / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015415:Biomarkers; D016207:Cytokines; D020381:Interleukin-17; D053583:Interleukin-1beta; D012333:RNA, Messenger; D020395:Receptors, Interleukin-7; D014409:Tumor Necrosis Factor-alpha