Amplification of IL-21 signalling pathway through bruton's tyrosine kinase in human B cell activation

Sheau Pey Wang, Shigeru Iwata, Shingo Nakayamada, Hiroaki Niiro, Siamak Jabbarzadeh-Tabrizi, Masahiro Kondo, Satoshi Kubo, Maiko Yoshikawa, Yoshiya Tanaka

研究成果: ジャーナルへの寄稿記事

18 引用 (Scopus)

抄録

Objective. B cells play an important role in the pathogenesis of autoimmune diseases. The role of Bruton's tyrosine kinase (Btk) in cytokine-induced human B cell differentiation and class-switch recombination remains incompletely defined. This study analysed the effect of Btk on human activated B cells. Methods. Purified B cells from healthy subjects were stimulated with B cell receptor (BCR) and other stimuli with or without a Btk inhibitor and gene expression was measured. The B cell line BJAB was used to assess Btk-associated signalling cascades. Phosphorylated Btk (p-Btk) in peripheral blood B cells obtained from 10 healthy subjects and 41 patients with RA was measured by flow cytometry and compared with patient backgrounds. Results. IL-21 signalling, in concert with BCR, CD40 and BAFF signals, led to robust expression of differentiation- and class-switch DNA recombination-related genes and IgG production in human B cells, all of which were significantly suppressed by the Btk inhibitor. Although phosphorylation of STAT1 and STAT3 was induced by co-stimulation with IL-21, BCR and CD40, STAT1 phosphorylation in the nucleus, but not in the cytoplasm, was exclusively impaired by Btk blockade. High levels of p-Btk were noted in B cells of RA patients compared with controls and they correlated significantly with titres of RF among RF-positive patients. Conclusion. The findings elucidate a model in which Btk not only plays a fundamental role in the regulation of BCR signalling, but may also mediate crosstalk with cytokine signalling pathways through regulation of IL-21-induced phosphorylation of STAT1 in the nuclei of human B cells. Btk appears to have pathological relevance in RA.

元の言語英語
記事番号keu532
ページ(範囲)1488-1497
ページ数10
ジャーナルRheumatology (United Kingdom)
54
発行部数8
DOI
出版物ステータス出版済み - 5 5 2015

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B-Lymphocytes
Phosphorylation
interleukin-21
Agammaglobulinaemia tyrosine kinase
Genetic Recombination
B-Cell Activation Factor Receptor
Healthy Volunteers
Cytokines
Autoimmune Diseases
Cell Differentiation
Blood Cells
Flow Cytometry
Cytoplasm
Immunoglobulin G
Gene Expression
Cell Line
DNA

All Science Journal Classification (ASJC) codes

  • Rheumatology
  • Pharmacology (medical)

これを引用

Wang, S. P., Iwata, S., Nakayamada, S., Niiro, H., Jabbarzadeh-Tabrizi, S., Kondo, M., ... Tanaka, Y. (2015). Amplification of IL-21 signalling pathway through bruton's tyrosine kinase in human B cell activation. Rheumatology (United Kingdom), 54(8), 1488-1497. [keu532]. https://doi.org/10.1093/rheumatology/keu532

Amplification of IL-21 signalling pathway through bruton's tyrosine kinase in human B cell activation. / Wang, Sheau Pey; Iwata, Shigeru; Nakayamada, Shingo; Niiro, Hiroaki; Jabbarzadeh-Tabrizi, Siamak; Kondo, Masahiro; Kubo, Satoshi; Yoshikawa, Maiko; Tanaka, Yoshiya.

:: Rheumatology (United Kingdom), 巻 54, 番号 8, keu532, 05.05.2015, p. 1488-1497.

研究成果: ジャーナルへの寄稿記事

Wang, SP, Iwata, S, Nakayamada, S, Niiro, H, Jabbarzadeh-Tabrizi, S, Kondo, M, Kubo, S, Yoshikawa, M & Tanaka, Y 2015, 'Amplification of IL-21 signalling pathway through bruton's tyrosine kinase in human B cell activation', Rheumatology (United Kingdom), 巻. 54, 番号 8, keu532, pp. 1488-1497. https://doi.org/10.1093/rheumatology/keu532
Wang, Sheau Pey ; Iwata, Shigeru ; Nakayamada, Shingo ; Niiro, Hiroaki ; Jabbarzadeh-Tabrizi, Siamak ; Kondo, Masahiro ; Kubo, Satoshi ; Yoshikawa, Maiko ; Tanaka, Yoshiya. / Amplification of IL-21 signalling pathway through bruton's tyrosine kinase in human B cell activation. :: Rheumatology (United Kingdom). 2015 ; 巻 54, 番号 8. pp. 1488-1497.
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abstract = "Objective. B cells play an important role in the pathogenesis of autoimmune diseases. The role of Bruton's tyrosine kinase (Btk) in cytokine-induced human B cell differentiation and class-switch recombination remains incompletely defined. This study analysed the effect of Btk on human activated B cells. Methods. Purified B cells from healthy subjects were stimulated with B cell receptor (BCR) and other stimuli with or without a Btk inhibitor and gene expression was measured. The B cell line BJAB was used to assess Btk-associated signalling cascades. Phosphorylated Btk (p-Btk) in peripheral blood B cells obtained from 10 healthy subjects and 41 patients with RA was measured by flow cytometry and compared with patient backgrounds. Results. IL-21 signalling, in concert with BCR, CD40 and BAFF signals, led to robust expression of differentiation- and class-switch DNA recombination-related genes and IgG production in human B cells, all of which were significantly suppressed by the Btk inhibitor. Although phosphorylation of STAT1 and STAT3 was induced by co-stimulation with IL-21, BCR and CD40, STAT1 phosphorylation in the nucleus, but not in the cytoplasm, was exclusively impaired by Btk blockade. High levels of p-Btk were noted in B cells of RA patients compared with controls and they correlated significantly with titres of RF among RF-positive patients. Conclusion. The findings elucidate a model in which Btk not only plays a fundamental role in the regulation of BCR signalling, but may also mediate crosstalk with cytokine signalling pathways through regulation of IL-21-induced phosphorylation of STAT1 in the nuclei of human B cells. Btk appears to have pathological relevance in RA.",
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AU - Wang, Sheau Pey

AU - Iwata, Shigeru

AU - Nakayamada, Shingo

AU - Niiro, Hiroaki

AU - Jabbarzadeh-Tabrizi, Siamak

AU - Kondo, Masahiro

AU - Kubo, Satoshi

AU - Yoshikawa, Maiko

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N2 - Objective. B cells play an important role in the pathogenesis of autoimmune diseases. The role of Bruton's tyrosine kinase (Btk) in cytokine-induced human B cell differentiation and class-switch recombination remains incompletely defined. This study analysed the effect of Btk on human activated B cells. Methods. Purified B cells from healthy subjects were stimulated with B cell receptor (BCR) and other stimuli with or without a Btk inhibitor and gene expression was measured. The B cell line BJAB was used to assess Btk-associated signalling cascades. Phosphorylated Btk (p-Btk) in peripheral blood B cells obtained from 10 healthy subjects and 41 patients with RA was measured by flow cytometry and compared with patient backgrounds. Results. IL-21 signalling, in concert with BCR, CD40 and BAFF signals, led to robust expression of differentiation- and class-switch DNA recombination-related genes and IgG production in human B cells, all of which were significantly suppressed by the Btk inhibitor. Although phosphorylation of STAT1 and STAT3 was induced by co-stimulation with IL-21, BCR and CD40, STAT1 phosphorylation in the nucleus, but not in the cytoplasm, was exclusively impaired by Btk blockade. High levels of p-Btk were noted in B cells of RA patients compared with controls and they correlated significantly with titres of RF among RF-positive patients. Conclusion. The findings elucidate a model in which Btk not only plays a fundamental role in the regulation of BCR signalling, but may also mediate crosstalk with cytokine signalling pathways through regulation of IL-21-induced phosphorylation of STAT1 in the nuclei of human B cells. Btk appears to have pathological relevance in RA.

AB - Objective. B cells play an important role in the pathogenesis of autoimmune diseases. The role of Bruton's tyrosine kinase (Btk) in cytokine-induced human B cell differentiation and class-switch recombination remains incompletely defined. This study analysed the effect of Btk on human activated B cells. Methods. Purified B cells from healthy subjects were stimulated with B cell receptor (BCR) and other stimuli with or without a Btk inhibitor and gene expression was measured. The B cell line BJAB was used to assess Btk-associated signalling cascades. Phosphorylated Btk (p-Btk) in peripheral blood B cells obtained from 10 healthy subjects and 41 patients with RA was measured by flow cytometry and compared with patient backgrounds. Results. IL-21 signalling, in concert with BCR, CD40 and BAFF signals, led to robust expression of differentiation- and class-switch DNA recombination-related genes and IgG production in human B cells, all of which were significantly suppressed by the Btk inhibitor. Although phosphorylation of STAT1 and STAT3 was induced by co-stimulation with IL-21, BCR and CD40, STAT1 phosphorylation in the nucleus, but not in the cytoplasm, was exclusively impaired by Btk blockade. High levels of p-Btk were noted in B cells of RA patients compared with controls and they correlated significantly with titres of RF among RF-positive patients. Conclusion. The findings elucidate a model in which Btk not only plays a fundamental role in the regulation of BCR signalling, but may also mediate crosstalk with cytokine signalling pathways through regulation of IL-21-induced phosphorylation of STAT1 in the nuclei of human B cells. Btk appears to have pathological relevance in RA.

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