JAK inhibitors impair GM-CSF-mediated signaling in innate immune cells.
BMC Immunol
; 21(1): 35, 2020 06 15.
Article
en En
| MEDLINE
| ID: mdl-32539713
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-1ß production by human neutrophils. However, the inhibitory effects of baricitinib on IL-1ß 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.Palabras clave
Texto completo:
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Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
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Factor Estimulante de Colonias de Granulocitos y Macrófagos
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Inhibidores de las Cinasas Janus
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Inmunidad Innata
Límite:
Humans
Idioma:
En
Año:
2020
Tipo del documento:
Article