Interleukin 6 plays a key role in the development of antigen-induced arthritis

Abstract

To investigate the direct role of interleukin (IL) 6 in the development of rheumatoid arthritis, IL-6-deficient (IL-6 ؊͞؊) mice were backcrossed for eight generations into C57BL͞6 mice, a strain of mice with a genetic background of susceptibility for antigen-induced arthritis (AIA). Both histological and immunological comparisons were made between IL-6-deficient (IL-6 ؊͞؊) mice and wild-type (IL-6 ؉͞؉) littermates after the induction of AIA. Although all IL-6 ؉͞؉ mice developed severe arthritis, only mild arthritis was observed in IL-6 ؊͞؊ mice. Safranin O staining demonstrated that articular cartilage was well preserved in IL-6 ؊͞؊ mice, whereas it was destroyed completely in IL-6 ؉͞؉ mice. In addition, comparable mRNA expression for both IL-1␤ and tumor necrosis factor ␣, but not for IL-6, was detected in the inf lamed joints of IL-6 ؊͞؊ mice, suggesting that IL-6 may play a more crucial role in cartilage destruction than either IL-1␤ or tumor necrosis factor ␣. In immunological comparisons, both antigen-specific in vitro proliferative response in lymph node cells and in vivo antibody production were elicited in IL-6 ؊͞؊ mice, but they were reduced to less than half of that found in IL-6 ؉͞؉ mice. Lymph node cells of IL-6 ؊͞؊ mice produced many more Th2 cytokines than did IL-6 ؉͞؉ mice with either antigen-specific or nonspecific stimulation in in vitro culture. Taken together, these results indicate that IL-6 may play a key role in the development of AIA at the inductive as well as the effector phase, and the blockade of IL-6 is possibly beneficial in the treatment of rheumatoid arthritis.

The p38‐Mediated Rapid Down‐Regulation of Cell Surface gp130 Expression Impairs Interleukin‐6 Signaling in the Synovial Fluid of Juvenile Idiopathic Arthritis Patients

“…The previous finding that experimental arthritis cannot be induced in IL-6-deficient mice (24,25) further supports the notion that IL-6 has a pathogenic role. Interestingly, the administration of IL-6 alone is not sufficient to restore the disease; restoration of the disease can be accomplished by administering a fusion protein comprising soluble IL-6R (sIL-6R) and .…”

IL-6 Is Required for the Development of Th1 Cell-Mediated Murine Colitis

“…Furthermore, IL-6 is produced by various kinds of cells following IL-1 and TNF-␣ stimulation (13). IL-6 is considered to play a central role in the regulation of inflammatory and immune reactions, and the requirement for IL-6 has been demonstrated for murine models of rheumatoid arthritis and multiple sclerosis (14,15). CD shares characteristics with these diseases in terms of oligoclonal expansion, activation of CD4 ϩ T cells, and participation of proinflammatory cytokines.…”

Targeting the interleukin‐6 receptor: A new treatment for systemic juvenile idiopathic arthritis?

“…In several models, IL-6 Ϫ/Ϫ mice are protected from arthritis (53)(54)(55)(56)(57). In these models, an absence or significant reduction of the inflammatory infiltrate is observed.…”