The role of TNF-alpha in the pathogenesis of inflammation and joint destruction in rheumatoid arthritis (RA): a study using a human RA/SCID mouse chimera.
OBJECTIVE
In order to elucidate which cytokine preferentially stimulates the synovium in patients with rheumatoid arthritis (RA), we investigated the roles of tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) using SCID mice engrafted with human RA tissue (SCID-HuRAg).


METHODS
The SCID-HuRAg mice were prepared according to our previously described method. First, SCID-HuRAg mice were treated with chimeric anti-TNF-alpha monoclonal antibody (mAb, 100 microg/mouse) and histological changes were examined 4 weeks after the initial treatment. Secondly, a total of 100 microg of recombinant TNF-alpha or IL-6 (0.6 microg/h) was administered daily to mice using an osmium pump. The histological changes and serum cytokine levels were examined 4 weeks after the initial administration. Human immunoglobulin G (IgG) was administered to mice as a control.


RESULTS
Synovial inflammatory cells were significantly decreased after the anti-TNF-alpha mAb treatment; conversely, the degree of synovial inflammation was significantly exacerbated by TNF-alpha administration. The levels of both IL-6 and TNF-alpha in sera were significantly increased by recombinant TNF-alpha administration, while TNF-alpha levels were unchanged by IL-6 administration. This suggests that TNF-alpha controls IL-6 production. Despite the profound changes in inflammation, we found no effects on bone and no articular cartilage damage was produced by TNF-alpha.


CONCLUSIONS
This study provides strong evidence that TNF-alpha is a key molecule in the control of the inflammatory changes that occur in the RA synovium. In addition, TNF-alpha regulates IL-6 production. However, other inflammatory pathways independent of TNF-alpha may contribute to the bone and cartilage damage seen in RA.
Matsuno
H
H
Department of Orthopedic Surgery, Toyama Medical and Pharmaceutical University, Toyama, UK.
Yudoh
K
K
Katayama
R
R
Nakazawa
F
F
Uzuki
M
M
Sawai
T
T
Yonezawa
T
T
Saeki
Y
Y
Panayi
G S
GS
Pitzalis
C
C
Kimura
T
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002678:Chimera; D017077:Culture Media, Conditioned / Q000378:metabolism; D004195:Disease Models, Animal; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011994:Recombinant Proteins / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D017077:Culture Media, Conditioned; D015850:Interleukin-6; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha