Role of JAK/STAT pathway in IL-6-induced activation of vascular smooth muscle cells.
OBJECTIVE
IL-6, an inducer of the acute-phase response, is linked with the development of vascular disease and atherosclerosis. One mechanism likely involves direct effects of IL-6 on vascular smooth muscle cells (VSMC), for IL-6 can induce VSMC proliferation and the release of monocyte chemoattractant protein-1 (MCP-1). We hypothesized that this stimulation occurs via the JAK (janus-activated kinase)/STAT (signal and transducers and activators of transcription) signaling pathway.


METHODS
Rat VSMC were stimulated with IL-6 in the presence or absence of a JAK 2 inhibitor, and the activation of STAT 3 (by Western), MCP-1 (by ELISA) and DNA synthesis (by (3)H-thymidine incorporation) was determined.


RESULTS
IL-6 rapidly induced phosphorylation of STAT 3 in a dose- and time-dependent manner with a peak expression at 30 min. IL-6 also stimulated MCP-1 protein production and DNA synthesis dose dependently. 50 microM of AG490, a specific JAK 2 inhibitor, partially inhibited STAT 3 activation and MCP-1 production, with near complete inhibition of DNA synthesis.


CONCLUSIONS
The JAK/STAT pathway partially mediates IL-6-induced MCP-1 production and DNA synthesis in rat VSMC. These studies implicate a role of the JAK/STAT pathway in the development of vascular disease and atherosclerosis.
Watanabe
Susumu
S
Baylor College of Medicine, Houston, Tex., USA. susumuw@showa-university-fujigaoka.gr.jp
Mu
Wei
W
Kahn
Andrew
A
Jing
Naijie
N
Li
Jin H
JH
Lan
Hui Y
HY
Nakagawa
Takahiko
T
Ohashi
Ryuji
R
Johnson
Richard J
RJ
D000818:Animals; D001011:Aorta / Q000166:cytology; D001161:Arteriosclerosis / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D053614:Janus Kinase 2; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D004247:DNA; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2