Cytokine profiles in mice with arthritis induced by anti-type II collagen monoclonal antibody plus lipopolysaccharide

Background: Anti-cytokine therapy is an effective therapy for rheumatoid arthritis. To know the kinetics of cytokine expression, we investigated mice with arthritis induced by anti-type II collagen monoclonal antibody (anti-CII Abs) plus lipopolysaccharide (LPS). Methods: BALB/c mice (7 weeks' age) were injected i.v. with anti-CII Abs 2 mg/mouse and 3 days later injected i.p. with 50 μ g of LPS. Mice developed arthritis, and the cytokine expressions in extracted legs were determined by RT-PCR. Serum cytokine concentrations were measured using ELISA. In addition, both sets of data were compared with those of TNF gene-deficient mice. Results: After induction of arthritis in wild-type mice, mRNA expression of TNF-α increased early, followed by IL-18. IL-1β and IL-6 mRNA expressions rose comparatively later. TNF-α, IL-1β and IL-6 concentrations in the serum reflected the level of their mRNA expressions. Interestingly, serum IL-18 level showed two distinct peaks, at early and later phase. In contrast, arthritis did not develop in TNF-α-deficient mice, and no elevation of IL-β or IL-6 in either serum or tissue mRNA was observed at any time point. Further, no increase in tissue mRNA levels was seen in TNF-α -deficient mice, however, there was a significant increase in serum IL-18 concentrations in the later phase. Conclusion: This study demonstrates that mRNA levels of TNF-α and IL-18 in both serum and joint tissue are increased, in the early phase with different patterns in mice with arthritis induced by anti-CII Abs plus LPS; IL-1β and IL-6 levels also increased in the later phase. The results using TNF-α -deficient mice indicate that TNF-α might play a crucial role as a key upstream molecule in the cytokine network of early inflammatory arthritis, and that TNF-α might trigger the synthesis of several other cytokines.