Effects of JAK Inhibitors Against JAK2-mediated Signaling in Innate Immune Cells

Yuya Fujita¹, Naoki Matsuoka¹, Makiko Furuya-Yashiro², Jumpei Temmoku², Yuki Kuroiwa³, Masaru Tanaka⁴, Tomoyuki Asano², Shuzo Sato⁵, Haruki Matsumoto², Hiroshi Watanabe², Hideko Kuzuru⁶, Hiroshi Yatsuhashi⁷, Atsushi Kawakami⁸ and Kiyoshi Migita⁹, ¹Fukushima Medical University School of Medicine, Department of Rheumatology, Fukushima, Fukushima, Japan, ²Fukushima Medical University School of Medicine, Department of Rheumatology, Fukushima, Japan, ³Eli Lilly Japan K.K., Tokyo, ⁴Eli Lilly Japan K.K., Tokyo, Japan, ⁵Fukushima Medical University School of Medicine, Department of Rheumatology, Fukushima, Japan, ⁶NHO Nagasaki Medical Center, Clinical Research Center, Omura, Japan, ⁷NHO Nagasaki Medical Center, Clinical Research Center, Omura, Nagasaki, Japan, ⁸Nagasaki University Graduate School of Biomedical Sciences, Unit of Advanced Preventive Medical Sciences, Department of Immunology and Rheumatology, Nagasaki, Nagasaki, Japan, ⁹Fukushima Medical University School of Medicine, Department of Rheumatology, Fukushima, Fukushima, Japan

Meeting: ACR Convergence 2020

Keywords: cytokines, Inflammation, innate immunity, rheumatoid arthritis, signal transduction

Session Information

Date: Sunday, November 8, 2020

Title: RA – Treatments Poster III: PROs, Biomarkers, Systemic Inflammation & Radiographs

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.

Disclosure: Y. Fujita, None; N. Matsuoka, None; M. Furuya-Yashiro, None; J. Temmoku, None; Y. Kuroiwa, Eli Lilly Japan K.K., 3; M. Tanaka, Eli Lilly Japan K.K, 3; T. Asano, None; S. Sato, None; H. Matsumoto, None; H. Watanabe, None; H. Kuzuru, None; H. Yatsuhashi, None; A. Kawakami, None; K. Migita, Eli Lilly Japan K.K., 2.

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 .

« Back to ACR Convergence 2020

ACR Meeting Abstracts - https://acrabstracts.org/abstract/effects-of-jak-inhibitors-against-jak2-mediated-signaling-in-innate-immune-cells/