JAK inhibitors impair GM-CSF-mediated signaling in innate immune cells
Posted on 2020-06-16 - 03:44
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.
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Fujita, Yuya; Matsuoka, Naoki; Temmoku, Jumpei; Furuya-Yashiro, Makiko; Asano, Tomoyuki; Sato, Shuzo; et al. (2020). JAK inhibitors impair GM-CSF-mediated signaling in innate immune cells. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.5022527.v1
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AUTHORS (12)
YF
Yuya Fujita
NM
Naoki Matsuoka
JT
Jumpei Temmoku
MF
Makiko Furuya-Yashiro
TA
Tomoyuki Asano
SS
Shuzo Sato
HM
Haruki Matsumoto
HW
Hiroshi Watanabe
HK
Hideko Kozuru
HY
Hiroshi Yatsuhashi
AK
Atsushi Kawakami
KM
Kiyoshi Migita