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

Abstract

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.

• Authors: Yuya Fujita, Naoki Matsuoka, Jumpei Temmoku, Makiko Furuya-Yashiro, Tomoyuki Asano, Shuzo Sato, Haruki Matsumoto, Hiroshi Watanabe, Hideko Kozuru, Hiroshi Yatsuhashi, Atsushi Kawakami, Kiyoshi Migita
• Journal: BMC immunology (BMC Immunol) Vol. 21 Issue 1 Pg. 35 (06 15 2020) ISSN: 1471-2172 [Electronic] England
• PMID: 32539713 (Publication Type: Journal Article)

Chemical References

• 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

Topics

• Antirheumatic Agents (pharmacology)
• Arthritis, Rheumatoid (drug therapy, 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)