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) |
| 巻 | 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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All Science Journal Classification (ASJC) codes
- Rheumatology
- Pharmacology (medical)
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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
}
TY - JOUR
T1 - Amplification of IL-21 signalling pathway through bruton's tyrosine kinase in human B cell activation
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
AU - Tanaka, Yoshiya
PY - 2015/5/5
Y1 - 2015/5/5
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.
UR - http://www.scopus.com/inward/record.url?scp=84939548568&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84939548568&partnerID=8YFLogxK
U2 - 10.1093/rheumatology/keu532
DO - 10.1093/rheumatology/keu532
M3 - Article
C2 - 25724205
AN - SCOPUS:84939548568
VL - 54
SP - 1488
EP - 1497
JO - Rheumatology
JF - Rheumatology
SN - 1462-0324
IS - 8
M1 - keu532
ER -