Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2016 Aug 30;113(35):9852-7. doi: 10.1073/pnas.1610253113. Epub 2016 Aug 11.

Network pharmacology of JAK inhibitors.

Author information

1
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
2
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;
3
Inflammation and Immunology, Pfizer, Cambridge, MA 02139.
4
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; cbdm@hms.harvard.edu.

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.

KEYWORDS:

JAK inhibitor; systems pharmacology; tofacitinib

PMID:
27516546
PMCID:
PMC5024632
[Available on 2017-02-28]
DOI:
10.1073/pnas.1610253113
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center