title: Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction.
abstract: Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. No drug to date targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a JAK inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and the associated vascular pathology remains to be characterized.
  
  
  
  MRL/lpr lupus-prone mice were administered tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum levels of autoantibodies and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular traps (NETs) release, endothelium-dependent vasorelaxation, and endothelial differentiation were compared in treated and untreated mice.
  
  
  
  Treatment with tofacitinib led to significant improvement in measures of disease activity, including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of proinflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated the formation of NETs and significantly increased endothelium-dependent vasorelaxation and endothelial differentiation. The drug was effective in both preventive and therapeutic strategies.
  
  
  
  Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus, and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage.
authors.affiliation: Translational Immunology Section, Office of Science Technology (OST), NIAMS, NIH.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Furumoto
authors.affiliation: Systemic Autoimmunity Branch, NIAMS, NIH.
authors.forename: Carolyne K
authors.initials: CK
authors.lastname: Smith
authors.affiliation: Systemic Autoimmunity Branch, NIAMS, NIH.
authors.forename: Luz
authors.initials: L
authors.lastname: Blanco
authors.affiliation: Systemic Autoimmunity Branch, NIAMS, NIH.
authors.forename: Wenpu
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Biodata Mining and Discovery Section, OST, NIAMS, NIH.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Brooks
authors.affiliation: Lipoprotein Metabolism Section, NHLBI, NIH.
authors.forename: Seth G
authors.initials: SG
authors.lastname: Thacker
authors.affiliation: Lipoprotein Metabolism Section, NHLBI, NIH.
authors.forename: Zarzour
authors.initials: Z
authors.lastname: Abdalrahman
authors.affiliation: Molecular Immunology and Inflammation Branch, NIAMS, NIH.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sciumè
authors.affiliation: Translational Immunology Section, Office of Science Technology (OST), NIAMS, NIH.
authors.forename: Wanxia L
authors.initials: WL
authors.lastname: Tsai
authors.affiliation: Translational Immunology Section, Office of Science Technology (OST), NIAMS, NIH.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Trier
authors.affiliation: Translational Immunology Section, Office of Science Technology (OST), NIAMS, NIH.
authors.forename: Leti
authors.initials: L
authors.lastname: Nunez
authors.affiliation: Translational Immunology Section, Office of Science Technology (OST), NIAMS, NIH.
authors.forename: Laurel
authors.initials: L
authors.lastname: Mast
authors.affiliation: Diagnostic and Research Services Branch, Office of the Director, NIH.
authors.forename: Victoria
authors.initials: V
authors.lastname: Hoffmann
authors.affiliation: Lipoprotein Metabolism Section, NHLBI, NIH.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.affiliation: Molecular Immunology and Inflammation Branch, NIAMS, NIH.
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
authors.affiliation: Systemic Autoimmunity Branch, NIAMS, NIH.
authors.forename: Mariana J
authors.initials: MJ
authors.lastname: Kaplan
authors.affiliation: Translational Immunology Section, Office of Science Technology (OST), NIAMS, NIH.
authors.forename: Massimo
authors.initials: M
authors.lastname: Gadina
mesh_terms: D000818:Animals; D005260:Female; D008180:Lupus Erythematosus, Systemic / Q000150:complications* / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D010880:Piperidines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D014652:Vascular Diseases / Q000188:drug therapy* / Q000209:etiology* / Q000276:immunology
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib