G-CSF exerts dual effects on endothelial cells--opposing actions of direct eNOS induction versus indirect CRP elevation.
Granulocyte-colony stimulating factor (G-CSF) has been shown to have protective effects in the heart and brain. However, it may also be involved in the acute inflammatory response which may be harmful. The effects of G-CSF on endothelial cells (ECs) and the vasculature are mostly unknown. To study the possible dual effects of G-CSF on ECs, we investigated whether G-CSF induces release of C-reactive protein (CRP) by hepatocytes and whether the direct beneficial effects of G-CSF could protect ECs from the detrimental effects of CRP. G-CSF treatment significantly induced monocytes to produce IL-6, and culture supernatants of G-CSF-stimulated monocytes induced CRP production in hepatocytes. On the other hand, G-CSF directly promoted EC proliferation and migration and reversed the deleterious effects of CRP. In mechanistic analyses, G-CSF increased not only the protein expression of endothelial nitric oxide synthase (eNOS), but also its transcription. Furthermore, it enhanced eNOS phosphorylation and activation, leading to increased production of NO. Thus, G-CSF reversed the attenuated production of NO by CRP. These effects of G-CSF on eNOS transcription, translation, and activation were blunted by the PI3K inhibitor, suggesting that EC protective effects of G-CSF were associated with the activation of the Akt/eNOS pathway. In conclusion, although G-CSF induces an inflammatory reaction leading to CRP production, it has direct beneficial effects protecting ECs from the deleterious effects of CRP through activation of Akt/eNOS pathway, leading to an increase in NO production. Our data suggests that G-CSF may exert dual opposing effects on endothelial cells.
Park
Kyung-Woo
KW
Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Kwon
Yoo-Wook
YW
Cho
Hyun-Jai
HJ
Shin
Jung-Im
JI
Kim
Yong-Jin
YJ
Lee
Sang Eun
SE
Youn
Seock-Won
SW
Lee
Hyun-Chae
HC
Kang
Hyun-Jae
HJ
Shaul
Philip W
PW
Oh
Byung-Hee
BH
Park
Young-Bae
YB
Kim
Hyo-Soo
HS
D002097:C-Reactive Protein / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014158:Transcription, Genetic; D014945:Wound Healing
D015850:Interleukin-6; D016179:Granulocyte Colony-Stimulating Factor; D009569:Nitric Oxide; D002097:C-Reactive Protein; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases