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 (400nM) in THP-1 cells. Whereas compared with barcitinib or upadacitinib, the inhibitory effects of tofacitinib on the GM-CSF-induced JAK2/STAT5 phosphorylation were weak at lower concentrations ( < 100nM). All JAKi inhibited GM-CSF-induced IL-1b production by human neutrophils. However, the inhibitory effects of baricitinib on IL-1b production were larger compared to those of tofacitinib or upadacitinib at lower concentrations ( < 100nM). 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.
Differential effects of infliximab on absolute circulating blood leucocyte counts of innate immune cells in early and late rheumatoid arthritis patients
