title: 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.
  
  
  CONCLUSIONS
  Bcl-3 is involved in the development of Tfh cells and the pathogenesis of RA, presumably by inducing IL-21 production.
authors.affiliation: Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Meguro
authors.affiliation: Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Hosokawa
authors.affiliation: Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Sanayama
authors.affiliation: Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Furuta
authors.affiliation: Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takatori
authors.affiliation: Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Suto
authors.affiliation: Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Sakamoto
authors.affiliation: Kazusa DNA Research Institute, Chiba, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.affiliation: Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000473:pathology / Q000503:physiopathology*; D000081242:B-Cell Lymphoma 3 Protein; D016022:Case-Control Studies; D002478:Cells, Cultured; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology; D007378:Interleukins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D000098546:Interleukin-21
chemical_list: D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; C000631345:Bcl3 protein, mouse; D015850:Interleukin-6; D007378:Interleukins; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; D000098546:Interleukin-21