Vol.20 No.2

Original Article

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

Authors

Akihiro Ishizu1 , Asami Abe2 , Yukiko Miyatake2 , Tomohisa Baba2 , Chihiro Iinuma3 , Utano Tomaru2 , Takashi Yoshiki2

  • Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo 060-0812, Japan
  • Department of Pathology, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan
  • Graduate School of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo 060-0812, Japan
Received:

2 September 2009

Accepted:

7 October 2009

Published online:

14 November 2009

Full Text

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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.

Key words

CREB - IL-6 - Synovial cell - Rheumatoid arthritis