Journal
ARTHRITIS & RHEUMATOLOGY
Volume 67, Issue 10, Pages 2651-2660Publisher
WILEY
DOI: 10.1002/art.39266
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT)
- Japanese Government
- MEXT Leading Graduate School Program
- Chugai Pharmaceutical
- Bristol-Myers Squibb
- Mitsubishi Tanabe Pharma
- Grants-in-Aid for Scientific Research [15K09521, 26461486] Funding Source: KAKEN
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Objective. We have previously shown that expression of the Bcl-3 gene, a member of the IkB family, is down-regulated in CD4+ T cells from patients with rheumatoid arthritis (RA) following tocilizumab therapy. The objective of this study was to examine the role of Bcl-3 in the pathogenesis of RA. Methods. DNA microarray analysis was used to compare the signal intensity of Bcl-3 in CD41+ T cells from untreated RA patients and healthy controls. We examined the roles of interleukin-6 (IL-6)/ STAT-3 signaling in the induction of Bcl-3. In addition, we analyzed the gene expression profiles of Bcl-3-transduced CD4+ T cells by RNA sequencing. The effects of enforced expression as well as gene silencing of Bcl-3 on the development of follicular helper T (Tfh) cells were evaluated. Finally, we examined correlations between the signal intensities of Bcl-3 and Tfh cell-related genes in CD4+ T cells from untreated RA patients. Results. Bcl-3 levels were significantly higher in RA patients than in healthy controls. IL-6 induced Bcl-3 expression in CD41 T cells in a STAT-3-dependent manner. Transcriptome analysis revealed that the expression of Bcl-6, a master regulator of Tfh cell differentiation, was significantly up-regulated by the enforced Bcl-3 expression. The enforced Bcl-3 expression increased, but Bcl-3 silencing decreased, the numbers of IL-21-producing Tfh-like cells. Bcl-3 levels in CD4+ T cells from RA patients correlated positively with the levels of Tfh cell-related genes CXCR5, inducible costimulator, and achaete-scute homolog 2. Conclusion. Bcl-3 is involved in the development of Tfh cells and the pathogenesis of RA, presumably by inducing IL-21 production.
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