Abstract
Janus kinase (JAK) family members constitutively bound to cytokine receptors and play important roles in the cytokine signal transduction through the activation of the signal transducer and activator of transcription (STAT). Tofacitinib, which is selective for JAK1 and JAK3, is highly effective on rheumatoid arthritis (RA) indicating its wide spread as a common treatment tool for RA. Although the precise action of tofacitinib on the JAK/STAT pathway has been investigated in mouse, the exact mechanism of action under inflammatory conditions in humans remains unclear. We conducted two studies with human synovium and dendritic cells (DCs) and revealed that tofacitinib act on multilineage cells thereby inhibiting lymphocytes both directly and indirectly. Tofacitinib inhibited IL-17 and IFN-γ production by CD4+ T cells subsequently suppressing IL-6 and IL-8 production by RA synovial fibroblasts and CD14+ monocytes, with decreased cartilage destruction in a ex vivo human arthritis model (SCID-HuRAg). On the other hand, tofacitinib directly acted on DCs and suppressed inflammatory cytokine production and expression of co-stimulatory molecules by inhibiting the positive feedback loop consisted of type-I IFN. Consequently, tofacitinib suppressed the T-cell stimulatory capability of DCs. These results indicate the wide range of biological effect of tofacitinib that directly and indirectly affect acquired immunity.
