Modulation of human endothelial cell activation by antiproliferative cytokines: exploration of arachidonic acid and intracellular cytokine pathways as possible mechanisms of action.
Some cytokines are known to affect both proliferation and activation of cultured human endothelial cells (HEC). We compared the extent of these modifications when induced by several cytokines or by the monocyte-derived endothelial cell inhibitory factor (MECIF) activity. We measured as endothelial activation parameters the expression of endothelium-leukocyte adhesion receptor-1 (ELAM-1, E-selectin), major histocompatibility complex (MHC) class II antigens, interleukin 1 (IL-1), interleukin 6 (IL-6), and prostacyclin. To further investigate if a common or distinct intracellular mechanism was involved in the action of these effectors we studied the influence of indomethacin, a cyclooxygenase inhibitor, on the growth inhibition and the activation effects. Our results showed that IL-1 beta, tumor necrosis factor (TNF)alpha, and MECIF activity induced the expression of ELAM-1 on HEC membrane while transforming growth factor beta (TGF beta), IL-6, and gamma-interferon (IFN-gamma) showed no effect. However, MECIF activity did not induce MHC class II antigens on HEC surface. MECIF activity appeared to be immunologically distinct from IL-1 beta, TNF alpha, and TNF beta (lymphotoxin). IL-6 production by HEC was significantly increased only in the presence of IL-1 beta, TNF alpha, or MECIF activity. Intracellular IL-1 alpha and IL-1 beta levels were markedly enhanced by IL-1 beta and TNF alpha. MECIF activity, TNF alpha, and IL-1 beta significantly increased prostacyclin secretion whereas TGF beta, IL-6, and IFN-gamma showed no significant effect. Indomethacin did not significantly modify ELAM-1 induction and reduced in a nonsignificant manner the antiproliferative effect of MECIF activity, TNF alpha, IL-1 beta, and TGF beta. The effectors studied appeared to modulate differently the expression of endothelial products and activation markers in vitro, suggesting that their effects could be mediated through distinct intracellular pathways. The cyclooxygenase pathway of arachidonic acid metabolism could be involved in the growth inhibitory action of MECIF activity, TNF alpha, IL-1 beta, and TGF beta but an additional putative pathway might also be involved.
Delomenie
C
C
Laboratoire de Biologie Vasculaire et Cellulaire, INSERM U 294, Hôpital Lariboisière, Paris, France.
Wautier-Pepin
M P
MP
Chappey
O
O
Wautier
J L
JL
D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D019040:E-Selectin; D004730:Endothelium, Vascular / Q000187:drug effects*; D011464:Epoprostenol / Q000378:metabolism; D006681:HLA-D Antigens / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015815:Cell Adhesion Molecules; D019040:E-Selectin; D006681:HLA-D Antigens; D007375:Interleukin-1; D015850:Interleukin-6; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D011464:Epoprostenol