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Role of JAK-STAT signaling in the pathogenic behavior of fibroblast-like synoviocytes in rheumatoid arthritis: Effect of the novel JAK inhibitor peficitinib.
Eur J Pharmacol. 2020 Sep 05; 882:173238.EJ

Abstract

Rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLS) play a crucial role in the pathogenesis of RA. RA-FLS display passive pro-inflammatory responses and self-directed aggressive responses, such as pro-inflammatory mediator production, reduced apoptosis and formation of a thickened synovial lining. Evidence suggests a role for Janus kinase (JAK)-signal transducer and transcriptional activator (STAT) signaling in the passive response but the aggressive behavior of RA-FLS is poorly understood. The pharmacologic effects of the novel JAK inhibitor, peficitinib, on cytokine-induced intracellular signaling and self-directed aggressive behavior of RA-FLS (e.g., increased expression of apoptosis-resistant genes and sodium nitroprusside-induced apoptosis) were investigated and compared with approved JAK inhibitors. RA-FLS assembly to form a lining-like structure and pro-inflammatory mediator production was investigated in three-dimensional (3D)-micromass culture. Peficitinib inhibited STAT3 phosphorylation in RA-FLS following induction by interferon (IFN)-α2b, IFN-γ, interleukin (IL)-6, oncostatin M, and leukemia inhibitory factor in a concentration-related manner, and was comparable to approved JAK inhibitors, tofacitinib and baricitinib. Peficitinib and tofacitinib suppressed autocrine phosphorylation of STAT3 and expression of apoptosis-resistant genes, and promoted cell death. In 3D-micromass culture, peficitinib reduced multi-layered RA-FLS cells to a thin monolayer, an effect less pronounced with tofacitinib. Both compounds attenuated production of vascular endothelial growth factor-A, matrix metalloproteinases, IL-6 and tumor necrosis factor superfamily-11. This study confirmed the pathogenic role of uncontrolled JAK-STAT signaling in the aggressive and passive responses of RA-FLS that are critical for RA progression. The novel JAK inhibitor peficitinib suppressed the pro-inflammatory behavior of RA-FLS, accelerated cell death and abrogated thickening of the synovium.

Authors+Show Affiliations

Drug Discovery Research, Astellas Pharma Inc., 21 Miyukiga-oka, Tsukuba, Ibaraki, 305-8585, Japan. Electronic address: takashi.emori@astellas.com.Drug Discovery Research, Astellas Pharma Inc., 21 Miyukiga-oka, Tsukuba, Ibaraki, 305-8585, Japan; Alliance Laboratory for Advanced Medical Research, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan. Electronic address: michiko.kasahara@astellas.com.Drug Discovery Research, Astellas Pharma Inc., 21 Miyukiga-oka, Tsukuba, Ibaraki, 305-8585, Japan. Electronic address: shingo.sugahara@astellas.com.Department of Advanced Medicine for Rheumatic Diseases, 54 Kawara-cho, Shougo-in, Sakyo-ku, Kyoto, 606-8507, Japan. Electronic address: mohashim@kuhp.kyoto-u.ac.jp.Department of Orthopedic Surgery, Kyoto University Graduate School of Medicine, 54 Kawara-cho, Shougo-in, Sakyo-ku, Kyoto, 606-8507, Japan. Electronic address: hiromu@kuhp.kyoto-u.ac.jp.Alliance Laboratory for Advanced Medical Research, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan. Electronic address: snaru@mfour.med.kyoto-u.ac.jp.Drug Discovery Research, Astellas Pharma Inc., 21 Miyukiga-oka, Tsukuba, Ibaraki, 305-8585, Japan. Electronic address: y.higashi@healios.jp.Drug Discovery Research, Astellas Pharma Inc., 21 Miyukiga-oka, Tsukuba, Ibaraki, 305-8585, Japan. Electronic address: yasutomo.fujii@astellas.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32561292

Citation

Emori, Takashi, et al. "Role of JAK-STAT Signaling in the Pathogenic Behavior of Fibroblast-like Synoviocytes in Rheumatoid Arthritis: Effect of the Novel JAK Inhibitor Peficitinib." European Journal of Pharmacology, vol. 882, 2020, p. 173238.
Emori T, Kasahara M, Sugahara S, et al. Role of JAK-STAT signaling in the pathogenic behavior of fibroblast-like synoviocytes in rheumatoid arthritis: Effect of the novel JAK inhibitor peficitinib. Eur J Pharmacol. 2020;882:173238.
Emori, T., Kasahara, M., Sugahara, S., Hashimoto, M., Ito, H., Narumiya, S., Higashi, Y., & Fujii, Y. (2020). Role of JAK-STAT signaling in the pathogenic behavior of fibroblast-like synoviocytes in rheumatoid arthritis: Effect of the novel JAK inhibitor peficitinib. European Journal of Pharmacology, 882, 173238. https://doi.org/10.1016/j.ejphar.2020.173238
Emori T, et al. Role of JAK-STAT Signaling in the Pathogenic Behavior of Fibroblast-like Synoviocytes in Rheumatoid Arthritis: Effect of the Novel JAK Inhibitor Peficitinib. Eur J Pharmacol. 2020 Sep 5;882:173238. PubMed PMID: 32561292.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of JAK-STAT signaling in the pathogenic behavior of fibroblast-like synoviocytes in rheumatoid arthritis: Effect of the novel JAK inhibitor peficitinib. AU - Emori,Takashi, AU - Kasahara,Michiko, AU - Sugahara,Shingo, AU - Hashimoto,Motomu, AU - Ito,Hiromu, AU - Narumiya,Shuh, AU - Higashi,Yasuyuki, AU - Fujii,Yasutomo, Y1 - 2020/06/16/ PY - 2019/06/21/received PY - 2020/05/27/revised PY - 2020/05/29/accepted PY - 2020/6/21/pubmed PY - 2021/5/13/medline PY - 2020/6/21/entrez KW - Fibroblast-like synoviocytes KW - Janus kinase KW - Peficitinib KW - Rheumatoid arthritis KW - Signal transducer and activator of transcription SP - 173238 EP - 173238 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 882 N2 - Rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLS) play a crucial role in the pathogenesis of RA. RA-FLS display passive pro-inflammatory responses and self-directed aggressive responses, such as pro-inflammatory mediator production, reduced apoptosis and formation of a thickened synovial lining. Evidence suggests a role for Janus kinase (JAK)-signal transducer and transcriptional activator (STAT) signaling in the passive response but the aggressive behavior of RA-FLS is poorly understood. The pharmacologic effects of the novel JAK inhibitor, peficitinib, on cytokine-induced intracellular signaling and self-directed aggressive behavior of RA-FLS (e.g., increased expression of apoptosis-resistant genes and sodium nitroprusside-induced apoptosis) were investigated and compared with approved JAK inhibitors. RA-FLS assembly to form a lining-like structure and pro-inflammatory mediator production was investigated in three-dimensional (3D)-micromass culture. Peficitinib inhibited STAT3 phosphorylation in RA-FLS following induction by interferon (IFN)-α2b, IFN-γ, interleukin (IL)-6, oncostatin M, and leukemia inhibitory factor in a concentration-related manner, and was comparable to approved JAK inhibitors, tofacitinib and baricitinib. Peficitinib and tofacitinib suppressed autocrine phosphorylation of STAT3 and expression of apoptosis-resistant genes, and promoted cell death. In 3D-micromass culture, peficitinib reduced multi-layered RA-FLS cells to a thin monolayer, an effect less pronounced with tofacitinib. Both compounds attenuated production of vascular endothelial growth factor-A, matrix metalloproteinases, IL-6 and tumor necrosis factor superfamily-11. This study confirmed the pathogenic role of uncontrolled JAK-STAT signaling in the aggressive and passive responses of RA-FLS that are critical for RA progression. The novel JAK inhibitor peficitinib suppressed the pro-inflammatory behavior of RA-FLS, accelerated cell death and abrogated thickening of the synovium. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/32561292/Role_of_JAK_STAT_signaling_in_the_pathogenic_behavior_of_fibroblast_like_synoviocytes_in_rheumatoid_arthritis:_Effect_of_the_novel_JAK_inhibitor_peficitinib_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(20)30330-7 DB - PRIME DP - Unbound Medicine ER -