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

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Article numberkeu532
Pages (from-to)1488-1497
Number of pages10
JournalRheumatology (United Kingdom)
Volume54
Issue number8
DOIs
Publication statusPublished - May 5 2015

All Science Journal Classification (ASJC) codes

  • Rheumatology
  • Pharmacology (medical)

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