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Cyclic AMP response element-binding protein is implicated in IL-6 production from arthritic synovial cells

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Modern Rheumatology

Abstract

Overproduction of interleukin (IL)-6 from synovial cells is critically involved in the pathogenesis of rheumatoid arthritis (RA). Cyclic adenosine monophosphate (AMP) response element-binding protein (CREB), a leucine zipper transcription factor, is expressed at a high level in synovial cells of patients with RA. Although CREB transactivates IL-6 expression in vascular smooth muscle cells, the relation between CREB expression and IL-6 production from arthritic synovial cells remains unclear. In this study, to determine whether CREB is implicated in IL-6 production from arthritic synovial cells, a dominant negative molecule of activation transcription factor 1 (ATF-1) was transfected into synovial cells obtained from arthritic joints of env-pX rats. These transgenic rats carrying the env-pX gene of human T-cell leukemia virus type-1 develop destructive arthritis with high titers of serum rheumatoid factor and are thus regarded as a suitable model of RA. The dominant negative ATF-1 (ATF-1DN) constitutes a heterodimer with CREB and inhibits CREB function, as CREB/ATF-1DN heterodimers no longer bind to the target sequence of CREB. We showed that transfection of ATF-1DN significantly reduced IL-6 production from arthritic synovial cells. These findings suggest that CREB is implicated in IL-6 production from synovial cells and plays an important role in RA pathogenesis.

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Acknowledgments

This study was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Ministry of Health, Labour and Welfare of Japan, and Japan Rheumatism Foundation.

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Authors and Affiliations

  1. Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo, 060-0812, Japan

    Akihiro Ishizu

  2. Department of Pathology, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan

    Asami Abe, Yukiko Miyatake, Tomohisa Baba, Utano Tomaru & Takashi Yoshiki

  3. Graduate School of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo, 060-0812, Japan

    Chihiro Iinuma

Authors
  1. Akihiro Ishizu
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  2. Asami Abe
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  3. Yukiko Miyatake
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  4. Tomohisa Baba
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  5. Chihiro Iinuma
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  6. Utano Tomaru
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  7. Takashi Yoshiki
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Correspondence to Akihiro Ishizu.

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Ishizu, A., Abe, A., Miyatake, Y. et al. Cyclic AMP response element-binding protein is implicated in IL-6 production from arthritic synovial cells. Mod Rheumatol 20, 134–138 (2010). https://doi.org/10.1007/s10165-009-0245-2

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  • DOI: https://doi.org/10.1007/s10165-009-0245-2

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