Role of Bcl-3 in the development of follicular helper T cells and in the pathogenesis of rheumatoid arthritis.

Abstract

OBJECTIVE:

We have previously shown that expression of the Bcl-3 gene, a member of the IκB 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 CD4+ 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 CD4+ 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.

• Authors: Kazuyuki Meguro, Kotaro Suzuki, Junichi Hosokawa, Yoshie Sanayama, Shigeru Tanaka, Shunsuke Furuta, Kei Ikeda, Hiroaki Takatori, Akira Suto, Akemi Sakamoto, Osamu Ohara, Hiroshi Nakajima
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 67 Issue 10 Pg. 2651-60 (Oct 2015) ISSN: 2326-5205 [Electronic] United States
• PMID: 26138292 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015, American College of Rheumatology.

Chemical References

• B-Cell Lymphoma 3 Protein
• BCL3 protein, human
• Bcl3 protein, mouse
• Interleukin-6
• Interleukins
• Proto-Oncogene Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• Transcription Factors
• interleukin-21

Topics

• Animals
• Arthritis, Rheumatoid (pathology, physiopathology)
• B-Cell Lymphoma 3 Protein
• Case-Control Studies
• Cells, Cultured
• Humans
• Interleukin-6 (pharmacology, physiology)
• Interleukins (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Oligonucleotide Array Sequence Analysis
• Proto-Oncogene Proteins (physiology)
• STAT3 Transcription Factor (deficiency, genetics, physiology)
• Signal Transduction (physiology)
• T-Lymphocytes, Helper-Inducer (drug effects, pathology, physiology)
• Transcription Factors (physiology)