Anti-arthritic effect of E3 ubiquitin ligase, c-MIR, expression in the joints

Cellular modulator of immune recognition (c-MIR) is an E3 ubiquitin ligase that ubiquitinates MHC class II and CD86 for their endocytosis and subsequent lysosomal degradation. In accordance with their importance in antigen presentation, systemic c-MIR over-expression downmodulates adaptive immune responses. Rheumatoid arthritis (RA) is a chronic synovitis driven by autoimmunity in the joints. Since antigen-presenting cells, such as macrophages, dendritic cells (DCs) and rheumatoid factor-positive B cells are abundant in the rheumatoid synovial tissues, autoantigens released by tissue damage should be presented locally, leading to amplification of systemic arthritogenic immune responses. Assuming that inhibition of the antigen presentation in the synovial tissues should suppress systemic arthritis, we transferred the c-MIR gene to the hind leg synovial tissues from mice with type II collagen (CII)-induced arthritis, an animal model of RA. The gene was transferred adenovirally because adenoviruses can infect DC and macrophages in vivo. Unexpectedly, therapeutic effect was observed only in the treated joints. Splenocyte responses and serum antibodies against CII were not suppressed. Moreover, in vitro studies disclosed that c-MIR gene transfer suppressed IL-6 production from synovial fibroblasts stimulated with tumor necrosis factor (TNF)-alpha or IL-1 beta. Bone marrow-derived macrophages and DC from c-MIR transgenic mice were impaired in IL-6 and TNF-alpha production when stimulated with LPS. This suppression was controlled at the post-transcriptional level since their mRNA was not affected. These results have disclosed a new function of c-MIR, inhibition of inflammatory cytokine production. Induction of c-MIR in the joints could be a new therapeutic approach to the treatment of RA.