IL-1-Independent Role of IL-17 in Synovial Inflammation and Joint Destruction During Collagen-Induced Arthritis

Abstract

T cell IL-17 displays proinflammatory properties and is expressed in the synovium of patients with rheumatoid arthritis. Its contribution to the arthritic process has not been identified. Here, we show that blocking of endogenous IL-17 in the autoimmune collagen-induced arthritis model results in suppression of arthritis. Also, joint damage was significantly reduced. In contrast, overexpression of IL-17 enhanced collagen arthritis. Moreover, adenoviral IL-17 injected in the knee joint of type II collagen-immunized mice accelerated the onset and aggravated the synovial inflammation at the site. Radiographic and histologic analysis showed markedly increased joint destruction. Elevated levels of IL-1β protein were found in synovial tissue. Intriguingly, blocking of IL-1αβ with neutralizing Abs had no effect on the IL-17-induced inflammation and joint damage in the knee joint, implying an IL-1 independent pathway. This direct potency of IL-17 was underscored in the unabated IL-17-induced exaggeration of bacterial cell wall-induced arthritis in IL-1β−/− mice. In conclusion, this data shows that IL-17 contributes to joint destruction and identifies an IL-1-independent role of IL-17. These findings suggest IL-17 to be a novel target for the treatment of destructive arthritis and may have implications for tissue destruction in other autoimmune diseases.

Treatment with a neutralizing anti‐murine interleukin‐17 antibody after the onset of collagen‐induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion

“…A single injection with anti-IL-17 antibody seems to be much more efficient than treatment with the soluble IL-17 receptor (sIL-17R):Fc fusion protein, as previously described (17,18). Since the treatment protocols are not identical between our previous study and the present study, we also treated CIA mice with the sIL-17R:Fc fusion protein starting after the onset of CIA (4 injections on alternative days using the same dose as described in ref.…”

“…Interestingly, the effects of IL-17 on matrix degradation and synthesis were not dependent on IL-1␤ production by chondrocytes, and IL-1 receptor antagonist did not block IL-17-induced matrix release nor did it prevent the inhibition of matrix synthesis in vitro using porcine articular cartilage explants (31). Moreover, we recently identified an IL-1␤-independent role of IL-17 in the pathogenesis of arthritis in vivo (17). The downstream signaling pathways for IL-17 and IL-1␤ seem to be distinct, and differential activation of activator protein 1 members by IL-17 and IL-1␤ has been described (33).…”

“…Moreover, IL-17, IL-1␤, TNF␣, and RANKL activate the common transcription factor NF-B in a variety of cells. IL-17 can synergize with these cytokines (IL-1␤, TNF␣, and RANKL), but probably has direct activity as well (17,29). Since a subset of RA patients does not respond to neutralizing IL-1␤ or TNF␣, other factors, such as IL-17, may participate in the proinflammatory cytokine cascade.…”

“…Since the treatment protocols are not identical between our previous study and the present study, we also treated CIA mice with the sIL-17R:Fc fusion protein starting after the onset of CIA (4 injections on alternative days using the same dose as described in ref. 17). This treatment did not result in suppression of the arthritis score; however, radiographic analysis revealed a significant reduction of the degree of joint destruction.…”

“…IL-17 can stimulate the production of IL-1␤ and TNF␣ from macrophages (4) and triggers human synoviocytes to produce IL-6, IL-8, granulocytemacrophage colony-stimulating factor, and prostaglandin E 2 (2,16), suggesting that IL-17 could be an upstream mediator in the pathogenesis of arthritis. Early neutralization of endogenous IL-17 prior to the development of arthritis in the experimental arthritis model suppresses the onset of disease (17,18). Furthermore, IL-17 may be involved in tissue destruction.…”