Interleukin-4 induces lipogenesis in porcine endothelial cells, which in turn is critical for induction of protection against complement-mediated injury.
Interleukin (IL)-4 has been shown to induce protection in porcine vascular endothelial cells (ECs) from killing by human complement. This protection is dependent on the PI3K/Akt signaling pathway. In this study, we investigated mechanisms downstream of Akt and found that activation of the lipid biosynthesis pathway is required for protection from complement in ECs treated with IL-4. Cells incubated with IL-4 for 48 hours contained increased fatty acids and phospholipids but cholesterol was not increased when compared with medium-treated controls. The transcription factor SREBP-1, which regulates fatty acid synthesis, was found to be activated in extracts of ECs incubated with IL-4 for 6 hours. Finally, induction of protection from complement killing with IL-4 was fully prevented by the presence of the SREBP inhibitor 25-OH cholesterol. This study showed that IL-4 induces lipid biosynthesis in porcine ECs through activation of SREBP-1 and that the activation of this pathway is critical for IL-4 to induce protection of porcine ECs from killing by human complement. Further study of these mechanisms may provide new strategies for the prevention of complement-mediated vascular injury as it occurs in xenograft rejection.
Black
S M
SM
University of Minnesota, Department of Surgery, Minneapolis, Minnesota 55455, USA.
Schott
M E
ME
Benson
B A
BA
Rutherford
M S
MS
Young
B K Levay
BK
Dalmasso
A P
AP
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005227:Fatty Acids / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000494:pharmacology*; D054709:Lecithins / Q000096:biosynthesis; D009682:Magnetic Resonance Spectroscopy; D010715:Phosphatidylglycerols / Q000096:biosynthesis; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D013552:Swine
D005227:Fatty Acids; D054709:Lecithins; D010715:Phosphatidylglycerols; D051780:Sterol Regulatory Element Binding Protein 1; D015847:Interleukin-4; D003165:Complement System Proteins