Interleukin 6 Is Required for the Development of Collagen-induced Arthritis

TLDR

Interleukin‑6 is overproduced in rheumatoid arthritis joints and, through its stimulatory effects on immune cells, endothelial cells, osteoclasts, and synovial fibroblasts, is thought to drive disease development and clinical manifestations. The study ablated IL‑6 in two arthritis mouse models—collagen‑induced arthritis in DBA/1J mice and TNF‑α transgenic mice—by intercrossing an IL‑6 null mutation and monitored disease progression with clinical, histological, and biochemical assessments. IL‑6 deletion had no effect on TNF‑α transgenic arthritis but completely protected DBA/1J IL‑6−/− mice from CIA, reducing anti‑type II collagen antibodies and eliminating joint inflammation and damage, indicating that IL‑6 receptor antagonists could benefit rheumatoid arthritis patients.

Abstract

Interleukin-6 (IL-6) is overproduced in the joints of patients with rheumatoid arthritis (RA) and, based on its multiple stimulatory effects on cells of the immune system and on vascular endothelia, osteoclasts, and synovial fibroblasts, is believed to participate in the development and clinical manifestations of this disease. In this study we have analysed the effect of ablating cytokine production in two mouse models of arthritis: collagen-induced arthritis (CIA) in DBA/1J mice and the inflammatory polyarthritis of tumor necrosis factor α (TNF-α) transgenic mice. IL-6 was ablated by intercrossing an IL-6 null mutation into both arthritis-susceptible genetic backgrounds and disease development was monitored by measuring clinical, histological, and biochemical parameters. Two opposite responses were observed; while arthritis in TNF-α transgenic mice was not affected by inactivation of the IL-6 gene, DBA/1J, IL-6−/− mice were completely protected from CIA, accompanied by a reduced antibody response to type II collagen and the absence of inflammatory cells and tissue damage in knee joints. These results are discussed in the light of the present knowledge of cytokine networks in chronic inflammatory disorders and suggest that IL-6 receptor antagonists might be beneficial for the treatment of RA.