Persistence of interleukin 7 activity and levels on tumour necrosis factor alpha blockade in patients with rheumatoid arthritis.
OBJECTIVE
To identify the mechanism of interleukin (IL)7-stimulated tumour necrosis factor alpha (TNFalpha) production and to determine the relationship between intra-articular IL7 and TNFalpha expression levels in patients with rheumatoid arthritis (RA). In addition, the effect of TNFalpha blockade on IL7 activity and on IL7 levels was studied.


METHODS
The effect of IL7 on isolated CD4 T cells and CD14 monocytes/macrophages was studied. IL7 and TNFalpha levels were measured in the synovial fluid of patients with RA. In RA synovial tissue, IL7 and TNFalpha expression was assessed in addition to IL1beta, numbers of inflammatory cells and adhesion molecule expression. The extent to which TNFalpha blockade could prevent IL7-induced lymphocyte responses was studied in vitro. In addition, regulation of serum IL7 levels on anti-TNFalpha therapy (adalimumab) was studied.


RESULTS
IL7 induced cell contact-dependent TNFalpha production by cocultures of T cells and monocytes, but not by T cells and monocytes cultured separately. IL7 and TNFalpha levels in RA synovial fluid and synovial tissue significantly correlated. IL7-stimulated lymphocyte responses were not inhibited by TNFalpha blockade. Circulating IL7 levels were significantly reduced in patients who successfully responded to anti-TNFalpha treatment. However, IL7 levels persisted in non-responders.


CONCLUSIONS
The present data suggest that IL7 is an important inducer of T cell-dependent TNFalpha production in RA joints. This may contribute to the correlation of intra-articular IL7 and TNFalpha in these joints. Furthermore, the persistence of IL7-induced inflammatory activity on TNFalpha blockade in vitro and persistence of IL7 levels and disease activity in anti-TNFalpha non-responders suggest that IL7 might additionally promote TNFalpha-independent inflammation.
van Roon
Joel A G
JA
Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. J.vanRoon@umcutrecht.nl
Hartgring
Sarita A Y
SA
Wenting-van Wijk
Marion
M
Jacobs
Kim M G
KM
Tak
Paul-Peter
PP
Bijlsma
Johannes W J
JW
Lafeber
Floris P J G
FP
D000068879:Adalimumab; D000893:Anti-Inflammatory Agents / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D015851:Interleukin-7 / Q000097:blood / Q000276:immunology*; D053699:Interleukin-7 Receptor alpha Subunit / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D013582:Synovial Fluid / Q000737:chemistry / Q000276:immunology; D013583:Synovial Membrane / Q000737:chemistry / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology*
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha; D000068879:Adalimumab