Blockade of endogenous interleukin 12 results in suppression of murine streptococcal cell wall arthritis by enhancement of interleukin 10 and interleukin 1Ra.
OBJECTIVE
The goal of this study was to investigate the role of endogenous interleukin 12 (IL12) in acute murine streptococcal cell wall (SCW) arthritis.


METHODS
C57black/6 mice were injected intraperitoneally with rat anti-murine IL12 (C17.8), shortly before induction of arthritis by intra-articular injection of 25 microg SCW fragments into the right knee joint. Joint swelling and chondrocyte synthetic function was analysed several days after induction of SCW arthritis. Local cytokine profile was determined, protein by using ELISA and mRNA by RT-PCR technology. To confirm the findings at later time points, tissue chamber model of inflammation was used. Histology was performed to examine cell influx and cartilage damage.


RESULTS
Suppression of joint swelling was noted at days 2 and 4, whereas no suppressive effect of anti-IL12 was found at day 1. Severe inhibition of chondrocyte proteoglycan synthesis was seen at day 1 in both arthritic control and anti-IL12 treated mice. However, chondrocyte function was restored at day 4 of arthritis in the anti-IL12 injected animals, but not in the arthritic controls. Moreover, cell influx in synovial tissue and joint cavity was reduced by anti-IL12 treatment. Neutralisation of IL12 reduced the local levels of IL1beta, IL12 and interferon gamma, when examined shortly after induction of SCW arthritis, whereas tumour necrosis factor alpha levels were not affected. In contrast, IL10 and IL1Ra protein and mRNA levels were strongly up regulated in synovial tissues after IL12 blockade. Enhancement of IL10 and IL1Ra by anti-IL12 was confirmed in a tissue chamber model with SCW induced inflammation.


CONCLUSIONS
This study indicates that IL12 is a pro-inflammatory cytokine during onset of acute SCW arthritis. Balances of proinflammatory and anti-inflammatory cytokines were strongly improved by anti-IL12 treatment.
Joosten
L A
LA
Department of Rheumatology, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
Helsen
M M
MM
van Den Berg
W B
WB
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001170:Arthritis, Infectious / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D002473:Cell Wall / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000096:biosynthesis*; D013297:Streptococcus pyogenes / Q000276:immunology
D000911:Antibodies, Monoclonal; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D012795:Sialoglycoproteins; D016753:Interleukin-10; D018664:Interleukin-12