Abstract
Pathogenic T helper cells (TH) and macrophages have been implicated in the development of rheumatoid arthritis (RA), which can lead to severe synovial inflammation and bone destruction. A range of therapies have been widely used for RA, including specific monoclonal antibodies and chemical inhibitors against inflammatory cytokines produced by these cells. However, these have not been sufficient to meet the medical need. Here, we show that in transgenic mice expressing truncated IK (tIK) cytokine, inflammatory arthritis symptoms were ameliorated as the result of suppression of the differentiation of TH1 and TH17 cells and of macrophage activation. During inflammatory responses, tIK cytokine systemically regulated macrophage functions and TH17 cell differentiation through inactivation of the MAPK and NF-κB pathways. Interestingly, the level of tIK cytokine was higher in synovial fluid of RA patients compared with that in osteoarthritis (OA) patients. Our observations suggest that tIK cytokine can counterbalance the induction of inflammatory cells related to RA and thus could be a new therapeutic agent for the treatment of RA.
Highlights
Immune cells, producing a cytokine storm, transiently induced IK cytokine expression and was able to downregulate expression of major histocompatibility complex (MHC) class II on B cells by increasing cAMP12
At 16 weeks, arthritis had developed in only 30% (3 of 10) of the tIK-IL-1 receptor antagonist knockout (IL1RaKO) mice compared with 100% (10 of 10) of the IL1RaKO mice (Fig. 1b)
We found that tIK-IL1RaKO mice showed lower percentages of IFN-γ-expressing, IL-4-expressing, and lower CD86+ expression on macrophages and IL-17-expressing CD4+ T helper cells (TH1, TH2, and TH17 cells, respectively) compared with the IL1RaKO mice (Fig. 1e,f)
Summary
Chronic inflammation associated with RA is critically dependent on an appropriate balance of pathogenic/regulatory immune cells and a break in self-tolerance[2,5,19]. IL1RaKO mice are a good model system to analyse the impact of tIK cytokine on pathogenic immune cells during the spontaneous development of arthritis. MAPK signalling pathways that are activated in immune cells under inflammatory conditions (Fig. 5f). This indicated that tIK cytokine has a homeostatic function in the immune response of inflammatory arthritis. We demonstrated that tIK cytokine functions as an upstream regulator of inflammatory cascades under stressed conditions. This means that tIK cytokine may have potential for treatment of humans, to be used instead of, or concurrent with, existing disease-modifying anti-rheumatic drugs
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