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Inhibition of JAK-STAT Signaling by Baricitinib Reduces Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal Cells

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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.

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Funding

This work was supported by the Grants-in-Aid for Scientific Research program of the Japanese Ministry of Education, Culture, Sports, Science, and Technology (No. 19K10311).

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Authors and Affiliations

  1. Department of Oral Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan

    Keiko Aota, Tomoko Yamanoi, Koichi Kani, Shinji Ono, Yukihiro Momota & Masayuki Azuma

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  1. Keiko Aota
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  2. Tomoko Yamanoi
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  3. Koichi Kani
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  4. Shinji Ono
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  6. Masayuki Azuma
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Contributions

Keiko Aota and Masayuki Azuma contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Keiko Aota, Tomoko Yamanoi, Koichi Kani, Shinji Ono, and Yukihiro Momota. The first draft of the manuscript was written by Keiko Aota and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Keiko Aota.

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The authors declare that they have no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Board of Tokushima University Hospital (#2802) and with the 1964 Helsinki declaration and its later amendments.

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Written informed consent was obtained from all individual participants included in the study, and this process was documented by the Institutional Review Board of Tokushima University Hospital. The informed consent procedure was approved by the Ethics Committee of Tokushima University Hospital.

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Authorization has been given from all authors to use unpublished data.

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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 44, 206–216 (2021). https://doi.org/10.1007/s10753-020-01322-w

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