OBJECTIVE: Tofacitinib, which is a Janus kinase (JAK) inhibitor, has shown clinical effects in the treatment of rheumatoid arthritis. JAKs are important kinases in lymphocyte differentiation; however, their function in dendritic cells (DCs) is unknown. In this study, the function of JAKs in DCs was investigated with tofacitinib. METHODS: The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide (LPS) stimulation were investigated. In addition, its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA-positive T cells. RESULTS: Tofacitinib decreased expression of CD80/CD86 in a concentration-dependent manner in LPS-stimulated DCs; however, it did not affect HLA-DR expression. Tofacitinib suppressed tumour necrosis factor, interleukin (IL)-6 and IL-1β production without affecting transforming growth factor (TGF)-β and IL-10 production. Meanwhile, CD80/CD86 expression in DCs was enhanced by type I interferon (IFN) stimulation, and the LPS-induced CD80/CD86 expression was inhibited by an antibody to type I IFN receptor. Furthermore, tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor (IRF)-7, which is a transcription factor involved in CD80/CD86 and type I IFN expression. Tofacitinib also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2. CONCLUSIONS: Tofacitinib, a JAK1/JAK3 inhibitor, affected the activities of human DCs. It decreased CD80/CD86 expression and T cell stimulatory capability through suppression of type I IFN signalling. These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
OBJECTIVE:Tofacitinib, which is a Janus kinase (JAK) inhibitor, has shown clinical effects in the treatment of rheumatoid arthritis. JAKs are important kinases in lymphocyte differentiation; however, their function in dendritic cells (DCs) is unknown. In this study, the function of JAKs in DCs was investigated with tofacitinib. METHODS: The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide (LPS) stimulation were investigated. In addition, its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA-positive T cells. RESULTS:Tofacitinib decreased expression of CD80/CD86 in a concentration-dependent manner in LPS-stimulated DCs; however, it did not affect HLA-DR expression. Tofacitinib suppressed tumour necrosis factor, interleukin (IL)-6 and IL-1β production without affecting transforming growth factor (TGF)-β and IL-10 production. Meanwhile, CD80/CD86 expression in DCs was enhanced by type I interferon (IFN) stimulation, and the LPS-induced CD80/CD86 expression was inhibited by an antibody to type I IFN receptor. Furthermore, tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor (IRF)-7, which is a transcription factor involved in CD80/CD86 and type I IFN expression. Tofacitinib also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2. CONCLUSIONS:Tofacitinib, a JAK1/JAK3 inhibitor, affected the activities of human DCs. It decreased CD80/CD86 expression and T cell stimulatory capability through suppression of type I IFN signalling. These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Kent J Weinhold; Jack F Bukowski; Todd V Brennan; Robert J Noveck; Janet S Staats; Liwen Lin; Linda Stempora; Constance Hammond; Ann Wouters; Christopher F Mojcik; John Cheng; Mark Collinge; Michael I Jesson; Anasuya Hazra; Pinaki Biswas; Shuping Lan; James D Clark; Jennifer A Hodge Journal: Clin Immunol Date: 2018-03-05 Impact factor: 3.969
Authors: Hayley James; Grace L Paley; Richard Brasington; Philip L Custer; Todd P Margolis; Michael A Paley Journal: Am J Ophthalmol Case Rep Date: 2021-04-21