IK acts as an immunoregulator of inflammatory arthritis by suppressing TH17 cell differentiation and macrophage activation

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.

Recombinant Adeno-Associated Virus Expressing Truncated IK Cytokine Diminishes the Symptoms of Inflammatory Arthritis

“…Although our previous study showed that tIK is a candidate target for inflammatory arthritis treatment [4], we did not then have a method for delivery of exogenous tIK into patients. In this study, we developed the recombinant AAV2-tIK for this purpose and showed that it has potential as a therapeutic agent for suppressing the progression of inflammatory arthritis.…”

“…immunologically activated condition, but not in a normal condition [4]. Therefore, AAV2-tIK may not show any immunological response in a normal condition in the mouse.…”

“…Treatment of MRL/lpr mice with truncated IK (tIK) reduced renal damage through reduction of macrophage and T cell infiltration [3]. Our previous study showed that transgenic mice expressing tIK were resistant to the induction of inflammatory arthritis via a reduction in proinflammatory immune cells such as macrophages and pathogenic T helper 1 (Th1) and Th17 cells [4]. These previous reports indicated that tIK may be a candidate for treatment of inflammatory arthritis, such as RA.…”

“…We cloned the tIK gene fused with the hemagglutinin (HA) gene into the AAV2 viral vector and pcDNA3.1. The tIK-HA gene was obtained from a previous clone [4] viral genomes (vg)/ml of recombinant AAV2-tIK and transfection with pcDNA3.1-tIK (tIK-HA) as the positive control were confirmed. Recombinant AAV2-GFP as a negative control was purchased from Virovek.…”

Therapeutic Effect of Exogenous Truncated IK Protein in Inflammatory Arthritis

“…Our previous study demonstrated the effects of tIK on rheumatoid arthritis (RA) using three mouse models: interleukin (IL)-1 receptor antagonist knockout (IL1RaKO) mice, an autologous induced RA model, and IL1RaKO/tIK-transgenic mice, termed tIK-IL1RaKO mice [ 11 ]. We observed milder symptoms and lower severity of RA in tIK-IL1RaKO mice compared with IL1RaKO mice.…”