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Inhibition of JAK-STAT Signaling by Baricitinib Reduces Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal Cells.
Inflammation. 2021 Feb; 44(1):206-216.I

Abstract

Sjögren's syndrome (SS) is a chronic autoimmune disease targeting salivary and lacrimal glands. C-X-C motif chemokine ligand 10 (CXCL10) expression is upregulated in lip salivary glands (LSGs) of primary SS (pSS) patients, and CXCL10 involved in SS pathogenesis via immune-cell accumulation. Moreover, interferon (IFN)-γ enhances CXCL10 production via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. We investigated the effects of baricitinib, a selective JAK1/2 inhibitor, on both IFN-γ-induced CXCL10 production and immune-cell chemotaxis. We used immunohistochemical staining to determine the expression levels and localization of JAK1 and JAK2 in LSGs of SS patients (n = 12) and healthy controls (n = 3). We then evaluated the effect of baricitinib in an immortalized normal human salivary gland ductal (NS-SV-DC) cell line. Immunohistochemical analysis of LSGs from pSS patients revealed strong JAK1 and JAK2 expression in ductal and acinar cells, respectively. Baricitinib significantly inhibited IFN-γ-induced CXCL10 expression as well as the protein levels in an immortalized human salivary gland ductal-cell clone in a dose-dependent manner. Additionally, western blot analysis showed that baricitinib suppressed the IFN-γ-induced phosphorylation of STAT1 and STAT3, with a stronger effect observed in the case of STAT1. It also inhibited IFN-γ-mediated chemotaxis of Jurkat T cells. These results suggested that baricitinib suppressed IFN-γ-induced CXCL10 expression and attenuated immune-cell chemotaxis by inhibiting JAK/STAT signaling, suggesting its potential as a therapeutic strategy for pSS.

Authors+Show Affiliations

Department of Oral Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan. aota.keiko@tokushima-u.ac.jp.Department of Oral Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan.Department of Oral Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan.Department of Oral Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan.Department of Oral Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan.Department of Oral Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32772240

Citation

Aota, Keiko, et al. "Inhibition of JAK-STAT Signaling By Baricitinib Reduces Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal Cells." Inflammation, vol. 44, no. 1, 2021, pp. 206-216.
Aota K, Yamanoi T, Kani K, et al. Inhibition of JAK-STAT Signaling by Baricitinib Reduces Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal Cells. Inflammation. 2021;44(1):206-216.
Aota, K., Yamanoi, T., Kani, K., Ono, S., Momota, Y., & Azuma, M. (2021). Inhibition of JAK-STAT Signaling by Baricitinib Reduces Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal Cells. Inflammation, 44(1), 206-216. https://doi.org/10.1007/s10753-020-01322-w
Aota K, et al. Inhibition of JAK-STAT Signaling By Baricitinib Reduces Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal Cells. Inflammation. 2021;44(1):206-216. PubMed PMID: 32772240.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of JAK-STAT Signaling by Baricitinib Reduces Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal Cells. AU - Aota,Keiko, AU - Yamanoi,Tomoko, AU - Kani,Koichi, AU - Ono,Shinji, AU - Momota,Yukihiro, AU - Azuma,Masayuki, PY - 2020/8/11/pubmed PY - 2021/10/8/medline PY - 2020/8/11/entrez KW - CXCL10 KW - IFN-γ KW - Janus kinase KW - Sjögren’s syndrome KW - baricitinib KW - salivary gland ductal cells SP - 206 EP - 216 JF - Inflammation JO - Inflammation VL - 44 IS - 1 N2 - Sjögren's syndrome (SS) is a chronic autoimmune disease targeting salivary and lacrimal glands. C-X-C motif chemokine ligand 10 (CXCL10) expression is upregulated in lip salivary glands (LSGs) of primary SS (pSS) patients, and CXCL10 involved in SS pathogenesis via immune-cell accumulation. Moreover, interferon (IFN)-γ enhances CXCL10 production via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. We investigated the effects of baricitinib, a selective JAK1/2 inhibitor, on both IFN-γ-induced CXCL10 production and immune-cell chemotaxis. We used immunohistochemical staining to determine the expression levels and localization of JAK1 and JAK2 in LSGs of SS patients (n = 12) and healthy controls (n = 3). We then evaluated the effect of baricitinib in an immortalized normal human salivary gland ductal (NS-SV-DC) cell line. Immunohistochemical analysis of LSGs from pSS patients revealed strong JAK1 and JAK2 expression in ductal and acinar cells, respectively. Baricitinib significantly inhibited IFN-γ-induced CXCL10 expression as well as the protein levels in an immortalized human salivary gland ductal-cell clone in a dose-dependent manner. Additionally, western blot analysis showed that baricitinib suppressed the IFN-γ-induced phosphorylation of STAT1 and STAT3, with a stronger effect observed in the case of STAT1. It also inhibited IFN-γ-mediated chemotaxis of Jurkat T cells. These results suggested that baricitinib suppressed IFN-γ-induced CXCL10 expression and attenuated immune-cell chemotaxis by inhibiting JAK/STAT signaling, suggesting its potential as a therapeutic strategy for pSS. SN - 1573-2576 UR - https://www.unboundmedicine.com/medline/citation/32772240/Inhibition_of_JAK_STAT_Signaling_by_Baricitinib_Reduces_Interferon_γ_Induced_CXCL10_Production_in_Human_Salivary_Gland_Ductal_Cells_ L2 - https://doi.org/10.1007/s10753-020-01322-w DB - PRIME DP - Unbound Medicine ER -