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1,25-Dihydroxyvitamin D₃ Induces CCR10 Expression in Terminally Differentiating Human B Cells¹

Department of Microbiology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan

In the B cell lineage, CCR10 is known to be selectively expressed by plasma cells, especially those secreting IgA. In this study, we examined the regulation of CCR10 expression in terminally differentiating human B cells. As reported previously, IL-21 efficiently induced the differentiation of activated human CD19⁺ B cells into IgD^–CD38⁺ plasma cells in vitro. A minor proportion of the resulting CD19⁺IgD^–CD38⁺ cells expressed CCR10 at low levels. 1,25-Dihydroxyvitamin D₃ (1,25-(OH)₂D₃), the active metabolite of vitamine D₃, dramatically increased the proportion of CD19⁺IgD^–CD38⁺ cells expressing high levels of CCR10. The 1,25-(OH)₂D₃ also increased the number of CCR10⁺ cells expressing surface IgA, although the majority of CCR10⁺ cells remained negative for surface IgA. Thus, 1,25-(OH)₂D₃ alone may not be sufficient for the induction of IgA expression in terminally differentiating human B cells. To further determine whether 1,25-(OH)₂D₃ directly induces CCR10 expression in terminally differentiating B cells, we next performed the analysis on the human CCR10 promoter. We identified a proximal Ets-1 site and an upstream potential vitamin D response element to be critical for the inducible expression of CCR10 by 1,25-(OH)₂D₃. We confirmed the specific binding of Ets-1 and 1,25-(OH)₂D₃-activated vitamin D receptor to the respective sites. In conclusion, 1,25-(OH)₂D₃ efficiently induces CCR10 expression in terminally differentiating human B cells in vitro. Furthermore, the human CCR10 promoter is cooperatively activated by Ets-1 and vitamin D receptor in the presence of 1,25-(OH)₂D₃.

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¹ This work was supported by a grant-in-aid from the Ministry of Education, Culture, Sports and Technology, Japan; by Solution-Oriented Research for Science and Technology from the Japan Science and Technology Corporation; and by the High-Tech Research Center Project for Private Universities: matching fund subsidy from the Ministry of Education, Culture, Sports, Science and Technology of Japan, 2002–2009.

² A.-K.S. and D.N. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Osamu Yoshie, Department of Microbiology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan. E-mail address: o.yoshie{at}med.kindai.ac.jp

⁴ Abbreviations used in this paper: ASC, Ab-secreting cell; 1,25-(OH)₂D₃, 1,25-dihydroxyvitamin D₃; DC, dendritic cell; GALT, gut-associated lymphoid tissue; HEK, human embryonic kidney; LCL, lymphoblastoid cell line; RA, all-trans retinoic acid; VDR, vitamin D receptor; VDRE, vitamin D response element.