title: Cyclic AMP response element-binding protein is implicated in IL-6 production from arthritic synovial cells.
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.
authors.affiliation: Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo, 060-0812, Japan. aishizu@med.hokudai.ac.jp
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ishizu
authors.forename: Asami
authors.initials: A
authors.lastname: Abe
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Miyatake
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Baba
authors.forename: Chihiro
authors.initials: C
authors.lastname: Iinuma
authors.forename: Utano
authors.initials: U
authors.lastname: Tomaru
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshiki
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051381:Rats; D055647:Rats, Transgenic; D013583:Synovial Membrane / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat