Date: Sunday, November 8, 2020
Session Type: Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Janus kinase (JAK) family is comprised of JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). JAKs form homo- or hetero-complexes, the combination of which plays crucial role in various cytokine signaling. JAK inhibitors (JAKis) have been approved for the treatment of RA. Granulocyte Macrophage colony-stimulating Factor (GM-CSF) could be implicated in the pathophysiology of RA by activating innate immune cells. We assessed the effects of isoform-specific JAKis on GM-CSF-primed human innate immune cells.
Methods: Human monocytic cell line, THP-1 cells or primary human neutrophils pretreated with tofacitinib (TOF), baricitinib (BAR) and upadacitinib (UPA) were stimulated with GM-CSF (20 ng/mL). JAK/ signal transducer and activator of transcription (STAT) phosphorylation and subsequent interleukin-1β (IL-1β) production were investigated using western blot and ELISA method.
Results: All JAKis blocked GM-CSF induced JAK2 phosphorylation at high concentration (400 nM) in THP-1 cells. BAR and UPA also inhibited JAK2 phosphorylation at lower concentrations (25 and 100 nM). Similarly, not TOF but BAR and UPA suppressed STAT5 phosphorylation at higher concentrations (100 and 400 nM) in THP-1 cells. BAR and UPA significantly suppressed the IL-1β at lower concentrations (25 and 100 nM) compared to TOF in THP-1 cells. Consistent with THP-1 cells, all JAKis inhibited IL-1β production at high concentration (400 nM) in human neutrophils. However, BAR significantly suppressed IL-1β at lower concentration (25 nM) compared to TOF in human neutrophils. All JAKis suppressed the expression of NLR family pyrin domain-containing 3 and casepase-1 (p20) release at high concentration (400 nM) whereas only BAR suppressed them even at lower concentration in human neutrophils.
Conclusion: The inhibition of JAK2-dependent cytokine signals varies depending on the type of JAKis. This suggests difference of JAK selectivity among JAKis may affect the modulation of innate immune cell activation.
To cite this abstract in AMA style:Fujita Y, Matsuoka N, Furuya-Yashiro M, Temmoku J, Kuroiwa Y, Tanaka M, Asano T, Sato S, Matsumoto H, Watanabe H, Kuzuru H, Yatsuhashi H, Kawakami A, Migita K. Effects of JAK Inhibitors Against JAK2-mediated Signaling in Innate Immune Cells [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/effects-of-jak-inhibitors-against-jak2-mediated-signaling-in-innate-immune-cells/. Accessed March 3, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effects-of-jak-inhibitors-against-jak2-mediated-signaling-in-innate-immune-cells/