title: JAK-inhibitor tofacitinib suppresses interferon alfa production by plasmacytoid dendritic cells and inhibits arthrogenic and antiviral effects of interferon alfa.
abstract: Tofacitinib is an oral Janus kinase inhibitor that is effective for the treatment of rheumatoid arthritis and shows encouraging therapeutic effects in several other autoimmune diseases. A prominent adverse effect of tofacitinib therapy is the increased risk of viral infections. Despite its advanced stage of clinical development, the modes of action that mediate the beneficial and adverse effects of tofacitinib in autoimmune diseases remain unclear. Interferon alfa (IFNα) produced by plasmacytoid dendritic cells (PDCs) is critically involved in the pathogenesis of many systemic autoimmune diseases and in immunity to viral infections. Using in vitro culture models with human cells, we studied the effects of tofacitinib on PDC survival and IFNα production, and on arthrogenic and antiviral effects of IFNα. Tofacitinib inhibited the expression of antiapoptotic BCL-A1 and BCL-XL in human PDC and induced PDC apoptosis. TLR7 stimulation upregulated the levels of antiapoptotic Bcl-2 family members and prevented the induction of PDC apoptosis by tofacitinib. However, tofacitinib robustly inhibited the production of IFNα by toll like receptor-stimulated PDC. In addition, tofacitinib profoundly suppressed IFNα-induced upregulation of TLR3 on synovial fibroblasts, thereby inhibiting their cytokine and protease production in response to TLR3 ligation. Finally, tofacitinib counteracted the suppressive effects of IFNα on viral replication. Tofacitinib inhibits PDC survival and IFNα production and suppresses arthrogenic and antiviral effects of IFNα signaling. Inhibition of the IFNα pathway at 2 levels may contribute to the beneficial effects of tofacitinib in autoimmune diseases and explain the increased viral infection rates observed during tofacitinib treatment.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Centre, Rotterdam, The Netherlands. Electronic address: p.boor@erasmusmc.nl.
authors.forename: Patrick P C
authors.initials: PPC
authors.lastname: Boor
authors.affiliation: Department of Surgery, Erasmus MC - University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Petra E
authors.initials: PE
authors.lastname: de Ruiter
authors.affiliation: Department of Rheumatology, Erasmus MC - University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Asmawidjaja
authors.affiliation: Department of Rheumatology, Erasmus MC - University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Lubberts
authors.affiliation: Department of Surgery, Erasmus MC - University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Luc J W
authors.initials: LJW
authors.lastname: van der Laan
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Kwekkeboom
mesh_terms: D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D016174:Hepacivirus / Q000502:physiology; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: D016898:Interferon-alpha; D007377:Interleukin-3; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D011758:Pyrroles; D050791:STAT Transcription Factors; C479163:tofacitinib