title: Network pharmacology of JAK inhibitors.
abstract: Small-molecule inhibitors of the Janus kinase family (JAKis) are clinically efficacious in multiple autoimmune diseases, albeit with increased risk of certain infections. Their precise mechanism of action is unclear, with JAKs being signaling hubs for several cytokines. We assessed the in vivo impact of pan- and isoform-specific JAKi in mice by immunologic and genomic profiling. Effects were broad across the immunogenomic network, with overlap between inhibitors. Natural killer (NK) cell and macrophage homeostasis were most immediately perturbed, with network-level analysis revealing a rewiring of coregulated modules of NK cell transcripts. The repression of IFN signature genes after repeated JAKi treatment continued even after drug clearance, with persistent changes in chromatin accessibility and phospho-STAT responsiveness to IFN. Thus, clinical use and future development of JAKi might need to balance effects on immunological networks, rather than expect that JAKis affect a particular cytokine response and be cued to long-lasting epigenomic modifications rather than by short-term pharmacokinetics.
authors: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors: Devapregasan
authors: D
authors: Moodley
authors: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors: Hideyuki
authors: H
authors: Yoshida
authors: Department of Statistics, University of British Columbia, Vancouver, BC, Canada V6T 1Z4; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z4;
authors: Sara
authors: S
authors: Mostafavi
authors: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors: Natasha
authors: N
authors: Asinovski
authors: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors: Adriana
authors: A
authors: Ortiz-Lopez
authors: Inflammation and Immunology, Pfizer, Cambridge, MA 02139.
authors: Peter
authors: P
authors: Symanowicz
authors: Inflammation and Immunology, Pfizer, Cambridge, MA 02139.
authors: Jean-Baptiste
authors: JB
authors: Telliez
authors: Inflammation and Immunology, Pfizer, Cambridge, MA 02139.
authors: Martin
authors: M
authors: Hegen
authors: Inflammation and Immunology, Pfizer, Cambridge, MA 02139.
authors: James D
authors: JD
authors: Clark
authors: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; cbdm@hms.harvard.edu.
authors: Diane
authors: D
authors: Mathis
authors: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; cbdm@hms.harvard.edu.
authors: Christophe
authors: C
authors: Benoist
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000276:immunology; D055261:Immunogenetic Phenomena / Q000187:drug effects / Q000235:genetics; D000075242:Janus Kinase Inhibitors / Q000494:pharmacology*; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects / Q000276:immunology
chemical_list: D016207:Cytokines; D000075242:Janus Kinase Inhibitors; D053612:Janus Kinases
keywords: JAK inhibitor; systems pharmacology; tofacitinib