Evidence map›Paper›PMID 27516546›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2016

Network pharmacology of JAK inhibitors.

Devapregasan Moodley, Hideyuki Yoshida, Sara Mostafavi, Natasha Asinovski, Adriana Ortiz-Lopez, Peter Symanowicz, Jean-Baptiste Telliez, Martin Hegen, James D Clark, Diane Mathis and 1 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
41citing papers in PubMed, 3 pooled it
4.1field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

41 citing papers in PubMed, 3 syntheses or guidelines pooled it, 66 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 3 institutions in 2 countries.

Devapregasan MoodleyDivision of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
Hideyuki YoshidaDivision of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
Sara MostafaviDepartment of Statistics, University of British Columbia, Vancouver, BC, Canada V6T 1Z4; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z4;
Natasha AsinovskiDivision of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
Adriana Ortiz-LopezDivision of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
Peter SymanowiczInflammation and Immunology, Pfizer, Cambridge, MA 02139.
Jean-Baptiste TelliezInflammation and Immunology, Pfizer, Cambridge, MA 02139.
Martin HegenInflammation and Immunology, Pfizer, Cambridge, MA 02139.
James D ClarkInflammation and Immunology, Pfizer, Cambridge, MA 02139.
Diane MathisDivision of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; cbdm@hms.harvard.edu.
Christophe BenoistDivision of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; cbdm@hms.harvard.edu.
Harvard University · USPfizer (United States) · USUniversity of British Columbia · CA

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

AnimalsCytokinesGene Regulatory NetworksImmunogenetic PhenomenaJanus Kinase InhibitorsJanus KinasesKiller Cells, NaturalMacrophagesMaleMice, Inbred C57BLSignal TransductionTranscriptomeCytokinesJanus Kinase InhibitorsJanus KinasesJAK inhibitorsystems pharmacologytofacitinib

Identifiers

PMID27516546
PMCPMC5024632
OpenAlexW2518284609

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.