The Importance of IL-1β and TNF-α, and the Noninvolvement of IL-6, in the Development of Monoclonal Antibody-Induced Arthritis

Abstract

Injection of anti-type II collagen Ab and LPS induces arthritis in mice. The levels of IL-1β, IL-6, and chemokines (macrophage inflammatory protein (MIP)-1α, 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-α 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-1β or TNF-α, 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-1β, TNF-α, or MIP-1α. 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-1β and TNF-α 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.

The role of CD69 in acute neutrophil‐mediated inflammation

“…At this time point, expression of TNF-a was very low (data not shown), confirming previous reports in CAIA [21] where its expression peaked at days 3 and 4, rapidly declining after this point. In contrast, the expression of TGF-b was reduced in inflamed hind paws of anti-CD69 mAbtreated mice.…”

“…Since the expression of IL-6, IL-1b, monocyte chemoattractant protein 1 (MCP-1) and TNF-a is correlated with the severity of arthritis in CAIA [21] and also in other arthritis experimental models, their expression was analyzed by quantitative real-time RT-PCR (Fig. 4).…”

Autoimmunity to citrullinated type II collagen in rheumatoid arthritis

“…These findings indicate that immunocomplexes composed of fragments of citrullinated type II collagen and autoantibodies were formed and deposited in the inflamed articular synovium of RA patients. Although it is unclear whether these immunocomplexes are involved in the induction of arthritis, it is known that systemic administration of a mixture of monoclonal anti-type II collagen antibodies induces arthritis in mice, 12 that major cytokines expressed in the articular synovium of RA patients, interleukin-1 and tumor necrosis factor-α, are predominantly expressed in the arthritic joints of these mice, 13 and that the immunocomplexes deposited in For all samples from RA patients, an inhibition assay was performed using citrullinated type II collagen as antigen these tissues activate the complement cascade, which is one of the first steps in the induction of inflammation. Therefore, these findings support the idea that the formation and subsequent deposition of citrullinated type II collagenautoantibody immunocomplexes in the synovium are involved in disease pathogenesis in RA patients, although there is a possibility that the immunocomplexes including the other citrullinated peptides except type II collagen also correlate the disease pathogenesis of RA.…”

Blocking of experimental arthritis by cleavage of IgG antibodies in vivo

“…Collagen antibody-induced arthritis (CAIA) is Fc␥ receptor dependent (3) and complement dependent (4), but not B cell or T cell dependent (5); neutrophils and macrophages are the major mediators of this inflammation (6), and secretion of tumor necrosis factor ␣ and interleukin-1␤ is pathogenic (7). CAIA provides an opportunity to study the inflammatory phase without involving the priming phase of the immune response.…”