Transforming growth factor-beta stimulates IL-1beta-induced monocyte chemoattractant protein-1 expression in human synovial cells via the ERK/AP-1 pathway.
OBJECTIVE
Transforming growth factor- beta (TGF-beta) has not only a fibrogenic role, but also monocyte/ macrophage chemotactic properties in a synovial joint. However, little is known about the effects of TGF-beta on monocyte chemoattractant protein-1 (MCP-1) expression in human synovial cells under inflammatory status. The aim of this study was to determine whether TGF-modulates MCP-1 production under the chronic inflammation, and to elucidate the cell signaling mechanism involved.


METHODS
Human synovial cells were exposed to IL-1beta, which mimics the environment of chronic inflammation. Production of MCP-1 protein and expression of MCP-1 mRNA were determined by ELISA and real-time PCR.


RESULTS
TGF-beta upregulated the expression of MCP-1 mRNA and protein with or without IL-1beta. TGF-beta and IL-1beta synergistically enhanced MCP-1 gene expression, and an AP-1 binding site was involved in the signal transduction. In addition, MEK inhibitor completely suppressed TGF-beta-induced MCP-1 production.


CONCLUSIONS
TGF-beta and IL-1beta synergistically enhance MCP-1 gene expression through the activation of the MEK/ERK1/2 pathways, which leads to AP-1 activation. The impairment of MCP-1 regulation by TGF-beta in resident synovial cells might represent an important mechanism of chronic inflammation and tissue fibrosis in a synovial joint. MCP-1 should be considered a valid target for therapeutic intervention.
Yoshimura
H
H
Department of Cellular Physiological Chemistry, Graduate School, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo, 113-8549, Japan.
Nakahama
K
K
Safronova
O
O
Tanaka
N
N
Muneta
T
T
Morita
I
I
D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta; D015291:Transforming Growth Factors
D018932:Chemokine CCL2; D053583:Interleukin-1beta; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D015291:Transforming Growth Factors