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-1? production by human neutrophils. However, the inhibitory effects of baricitinib on IL-1? 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.

SUBMITTER: Fujita Y 

PROVIDER: S-EPMC7296727 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature