JAK inhibitors impair GM-CSF-mediated signaling in innate immune cells

BMC Immunol. 2020 Jun 15;21(1):35. doi: 10.1186/s12865-020-00365-w.


Background: Innate immune cells play a crucial role in the pathophysiology of rheumatoid arthritis (RA) via release of cytokines. Small-molecule inhibitors of Janus kinases (JAKi) are clinically efficacious in patients with RA. However, the isoform-specific action of each JAKi is difficult to assess, since JAKs form heterodimeric complexes with cytokine receptors. We assessed the effects of several JAKi on GM-CSF-primed human innate immune cells.

Results: Treatment with JAKi (tofacitinib, baricitinib, upadacitinib) prevented GM-CSF-induced JAK2/STAT5 phosphorylation at higher concentrations (400 nM) in THP-1 cells. Whereas compared with baricitinib or upadacitinib, the inhibitory effects of tofacitinib on the GM-CSF-induced JAK2/STAT5 phosphorylation were weak at lower concentrations (≤ 100 nM). All JAKi inhibited GM-CSF-induced IL-1β production by human neutrophils. However, the inhibitory effects of baricitinib on IL-1β production were larger compared to those of tofacitinib or upadacitinib at lower concentrations (≤ 100 nM). Similarly, all JAKi inhibited GM-CSF-induced caspase-1(p20) production by human neutrophils.

Conclusion: We conclude that incubation with JAKi prevents GM-CSF-mediated JAK2/STAT5 activation in human innate immune cells. Although baricitinib and upadacitinib almost completely blocked GM-CSF-mediated JAK2/STAT5 signaling, the inhibitory effects of tofacitinib were weaker at lower concentrations suggesting that variation exists among these JAKi in the inhibition of JAK2 signaling pathways.

Keywords: Baricitinib; GM-CSF; IL-1β; Janus kinases; Rheumatoid arthritis; Tofacitinib; Upadacitinib.

MeSH terms

  • Antirheumatic Agents / pharmacology
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / metabolism
  • Azetidines / pharmacology
  • Cell Line
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Immunity, Innate / drug effects*
  • Janus Kinase 2 / metabolism
  • Janus Kinase Inhibitors / pharmacology*
  • Neutrophils / drug effects
  • Piperidines / pharmacology
  • Purines / pharmacology
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction / drug effects*
  • Sulfonamides / pharmacology
  • THP-1 Cells / immunology


  • Antirheumatic Agents
  • Azetidines
  • Heterocyclic Compounds, 3-Ring
  • Janus Kinase Inhibitors
  • Piperidines
  • Purines
  • Pyrazoles
  • Pyrimidines
  • STAT5 Transcription Factor
  • Sulfonamides
  • upadacitinib
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • tofacitinib
  • Janus Kinase 2
  • baricitinib