Involvement of cAMP responsive element binding protein (CREB) in the synovial cell hyperfunction in patients with rheumatoid arthritis.
OBJECTIVE
To elucidate a possible role of cAMP responsive element binding protein (CREB) in rheumatoid arthritis (RA) synovial cell function, we have studied CREB expression of synovial cells and the effects of an inhibitor of the cAMP/CREB signal pathway on synovial cell function in patients with RA.


METHODS
We examined CREB expression by immunohistochemical staining, immunocytochemical staining, and gel shift assays. Effects of cAMP/CREB inhibitor on the proliferation of RA synovial cells were assessed by [3H]-TdR incorporation, and those on proinflammatory cytokine and matrix metalloproteinase (MMP) production by reverse transcription PCR and ELISAs.


RESULTS
Immunohistochemical staining of synovial tissue revealed that CREB is expressed mainly in the lining and sublining layers of synovium in patients with RA. DNA binding activity of CREB was ascertained by a gel shift assay. We also confirmed nuclear translocation and phosphorylation of CREB in TNF-alpha stimulated RA fibroblast-like synovial cells by immunocytochemical staining. Modulators of cAMP/CREB signaling pathway, such as Rp-cAMP, had an inhibitory potential on RA synovial cell proliferation in vitro. Rp-cAMP also inhibited the proinflammatory cytokine and MMP production.


CONCLUSIONS
CREB is involved in the synovial cell activity in patients with RA. Inhibition of CREB activity by its inhibitor brings about the correction of aberrant synovial cell functions in patients with RA, thus suggesting a possible clinical application of cAMP/CREB inhibitors.
Takeba
Y
Y
Department of Immunology, St. Marianna University School of Medicine, Kanagawa, Japan.
Suzuki
N
N
Wakisaka
S
S
Takeno
M
M
Kaneko
A
A
Asai
T
T
Sakane
T
T
D000368:Aged; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D001692:Biological Transport / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D013873:Thionucleotides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D013873:Thionucleotides; D014409:Tumor Necrosis Factor-alpha; C016957:adenosine-3',5'-cyclic phosphorothioate; D000242:Cyclic AMP; D020782:Matrix Metalloproteinases