Tofacitinib enhances interferon-γ-induced expression of major histocompatibility complex class II in macrophages

Tofacitinib is the first selective Janus kinase (JAK) 1/3 inhibitor approved for the treatment of rheumatoid arthritis and has been demonstrated to exhibit its efficacy through suppression of lymphocyte activation. Although macrophages are critically involved in the pathogenesis of rheumatoid arthritis, little is known about the influence of tofacitinib on macrophage activation especially expression of major histocompatibility complex class II (MHC II) and co-stimulatory molecule CD86. In the present study, we examined the effect of tofacitinib on the expression of MHC II and CD86 in RAW264.7 murine macrophages. Interferon (IFN)-γ induces the cell surface expression of MHC II and CD86. The treatment of tofacitinib at 0.5 μM significantly upregulated IFN-γ-induced expression of MHC II, while decreased the expression of CD86. Hence the population of CD86^- MHC II⁺ cells that induced by tofacitinib at 0.5 μM in the presence of IFN-γ were approximately three times larger than that of IFN-γ alone. Consistent with the surface expression, tofacitinib enhanced IFN-γ-induced mRNA expression of MHC II, and contrarily, decreased that of CD86. Similarly, tofacitinib increased the mRNA expression of MHC II transactivator (CIITA), especially CIITA type I, which is a key regulator of MHC II gene transcription. These findings suggested that tofacitinib enhanced IFNγ-induced MHC II expression by transcriptional regulation through induction of CIITA in macrophages and raise the possibility that a novel action of tofacitinib.