Injection of anti-
type II collagen Ab and LPS induces
arthritis in mice. The levels of
IL-1 beta,
IL-6, and
chemokines (
macrophage inflammatory protein (MIP)-1 alpha, MIP-2, and
monocyte chemoattractant protein-1) in the hind paws increased with the onset of
arthritis and correlated highly with
arthritis scores. The level of
TNF-alpha was also elevated, but only transiently. Quantitative real-time PCR analysis revealed increases in
cytokine and
chemokine mRNA. To elucidate the contribution of inflammatory
cytokines and
chemokines in
arthritis development more directly,
recombinant proteins, neutralizing Abs, and knockout mice were used. The injection of rIL-1 beta or
TNF-alpha, but not
IL-6 or
chemokines, induced
arthritis when mice were i.v. preinjected with anti-
type II collagen Ab. However, a single injection of recombinant
cytokines or
chemokines into the hind paws did not induce swelling.
Arthritis development was inhibited by neutralizing Ab against
IL-1 beta,
TNF-alpha, or MIP-1 alpha. In contrast, the inhibitory effect by anti-MIP-2 Ab was partial and, surprisingly, Abs to
IL-6 and
monocyte chemoattractant protein-1 showed no inhibitory effect. Furthermore,
arthritis development in IL-1R(-/-) mice and TNFR(-/-) mice was not observed at all, but severe
arthritis was developed in IL-6(-/-) mice. These results suggest that
IL-1 beta and
TNF-alpha play more crucial roles than
IL-6 or
chemokines in this model. Because
arthritis was also developed in SCID mice, the development of
arthritis in the Ab-induced mice model is due to a mechanism that does not involve T or B cells.