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Tumor-necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine with a wide variety of biological effects. The most important source of this cytokine is monocytes/macrophages. It is a potent agonist in the activation of endothelial cells; however, the precise role of endothelial cells as a source of TNF-alpha is not known. In the present study, we addressed the possibility that TNF-alpha is produced by cultured human umbilical vein endothelial cells (HUVEC) stimulated with factors such as lipopolysaccharide (LPS) or interleukin-1alpha (IL-1alpha). LPS and IL-1alpha induced expression of TNF-alpha mRNA in HUVEC. IL-1alpha induced expression and secretion of TNF-alpha protein, but LPS did not induce production of TNF-alpha protein. Most of the TNF-alpha protein in cell lysate was found in the membrane fraction. The mRNA for TNF-alpha-converting enzyme (TACE) was expressed in unstimulated HUVEC, and its level was not altered by treatment with LPS or IL-1alpha. Transfection of HUVEC with full-length cDNA encoding the precursor TNF-alpha enhanced secretion of TNF-alpha protein by these cells, and treatment of the cells with a TACE inhibitor reduced the secretion. These results suggest that HUVEC produce TNF-alpha and have TACE activity. Secreted TNF-alpha may be involved in autocrine activation of endothelial cells, and TNF-alpha retained in cell membrane may serve as a juxtacrine system to activate target cells on the endothelial surface.
Imaizumi et al. (Tue,) studied this question.