TNF-alpha, IL-4, and IFN-gamma regulate differential expression of P- and E-selectin expression by porcine aortic endothelial cells.
P- and E-selectin are surface glycoproteins that mediate leukocyte rolling on the surface of endothelium in inflammation. We have cloned porcine P-selectin cDNA and generated a mAb, 12C5, with which to examine P-selectin expression by porcine aortic endothelial cells (PAEC) in comparison with that of E-selectin. Basal expression by PAEC of P-selectin was greater than that of E-selectin, whereas E-selectin expression was more prominently enhanced than that of P-selectin by stimulation with TNF-alpha or IL-1alpha. Both human or porcine IL-4 led to an increase in P-selectin expression, with kinetics that were delayed compared with those seen following stimulation with TNF-alpha or IL-1alpha, but IL-4 did not stimulate expression of E-selectin. When cells were stimulated with TNF-alpha in the presence of IL-4, we observed enhanced P-selectin expression with a parallel reduction in E-selectin expression. Finally, the increase in P-selectin expression due to human IL-4 was reduced in the presence of porcine but not human IFN-gamma. These observations show that E-selectin and P-selectin expression are differentially regulated in PAEC, and that IL-4 leads to a shift in the relative surface density of the two molecules toward P-selectin. The ability of porcine IFN-gamma to inhibit IL-4-induced P-selectin expression suggests that the balance between Th1 and Th2 cytokine production may determine the relative densities of the two selectins in chronic immune-mediated inflammation. Because the increased expression of P-selectin induced by human IL-4 was not inhibited by human IFN-gamma, this balance may be shifted toward P-selectin expression in porcine xenografts infiltrated by human lymphocytes.
Stocker
C J
CJ
British Heart Foundation Cardiovascular Medicine Unit, and Department of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Sugars
K L
KL
Harari
O A
OA
Landis
R C
RC
Morley
B J
BJ
Haskard
D O
DO
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis; D001011:Aorta; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000302:isolation & purification; D015536:Down-Regulation / Q000276:immunology; D019040:E-Selectin / Q000096:biosynthesis* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D007375:Interleukin-1 / Q000502:physiology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins / Q000502:physiology; D008969:Molecular Sequence Data; D019007:P-Selectin / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D013552:Swine; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
D000911:Antibodies, Monoclonal; D018076:DNA, Complementary; D019040:E-Selectin; D007375:Interleukin-1; D008024:Ligands; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma