Transcriptional regulation of CCR10 expression in plasma cells

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 17590443
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Kinki Univeristy
• Principal Investigator: YOSHIE Osamu Kinki Univeristy, School of Medicine, Professor, 医学部, 教授 (10166910)
• Co-Investigator(Kenkyū-buntansha): HIESHIMA Kunio Kinki Univeristy, School of Medicine, Lecturer, 医学部, 講師 (10322570) ; NAKAYAMA Takashi Kinki Univeristy, School of Medicine, Lecturer, 医学部, 講師 (60319663) ; NAGAKUBO Daisuke Kinki Univeristy, School of Medicine, Assistant, 医学部, 助手 (10368293) ; SHIRAKAWA Aiko-konno Kinki Univeristy, School of Medicine, Assistant, 医学部, 助手 (30260285)
• Project Period (FY): 2005 – 2006
• Keywords: plasma cell / CCR10 / mucosal immunity / transcription factor / IL-21 / vitamin D / Ets-1 / Vitamin D3 receptor

Research Abstract

CCR10 has been reported to be expressed by almost all IgA-secreting plasma cells, while its ligand CCL28 is widely expressed in various mucosal tissues. Thus, the CCR10-CCL28 system is likely to contribute a wide distribution of IgA-secreting plasma cells in the common mucosal immune system. Here we examined the mechanism of CCR10 expression in terminally differentiating B cells. As reported previously, activated human CD19^+ B cells treated with IL-21 efficiently differentiated into IgD^-CD38^+ plasma cells. Even though IgD^-CD38^+ cells did not spontaneously expressed CCR10, a substantial fraction turned to express CCR10 if the differentiation was induced in the presence of 1,25-dihydroxyvitamin D3 (1,25-(OH)_2D_3), which is known to promote common mucosal immune responses if used as an adjuvant. However, we observed little increases in IgA^+ cells by 1,25-(OH)_2D_3. To determine the transcriptional mechanism regulating 1,25-(OH)_2D_3-inducible expression of CCR10 in terminally differentiating B cells, we next carried out a series of analysis on the CCR10 promoter. The reporter assays involving a series of 5'-deleted promoter fragments and promoter fragments with site-directed mutations revealed that a proximal Ets-1 site and an upstream vitamin D3 response element (VDRE) were critical for CCR10 expression. The NoShift transcription factor binding assays using nuclear extracts from CCR10-expressing myeloma cell lines confirmed specific binding of Ets-1 and 1,25-(OH)_2D_3-activated vitamin D3 receptor (VDR) to the respective elements. Collectively, 1,25-(OH)2D3 efficiently induces CCR10 expression in IL-21-induced human plasma cells in vitro. Furthermore, the CCR10 promoter is cooperatively activated by 1,25-(OH)_2D_3-activated VDR and Ets-1.