Effects of Tumour Necrosis Factor and Related Cytokines on Vascular Endothelial Cells

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Abstract
Tumour necrosis factor (TNF) and related cytokines have been found to alter the phenotype of vascular endothelial cells so as to promote coagulation, inflammation and immunity. We have used recombinant human TNF, lymphotoxin (LT), interleukin 1α (IL‐1α) and interleukin 1β (IL‐1β) to study and compare the effects of these molecules on cultured human endothelial cells (HEC). All four mediators cause HEC monolayers to reorganize from an epithelioid to a fibroblastoid morphology. Reorganization is slow (days), reversible upon cytokine withdrawal and enhanced by co‐addition of immune interferon. Coincident with morphological change, TNF and LT (but not IL‐1α or IL‐1β) cause a marked increase in HLA‐A, B mRNA and antigen expression. TNF and LT also induce a slow increase in the mRNA levels and cell‐surface expression of IL‐1 species. All four cytokines have been reported to enhance HEC adhesiveness for lymphocytes and inflammatory leucocytes; these changes temporally coincide with a rapid (hours) and sustained increase in expression of intercellular adhesion molecule 1 (ICAM‐1), and with a rapid but transient de novo expression of an endothelial‐leucocyte adhesion molecule (detected by antibody H4/18), respectively. TNF and LT induce reciprocal tachyphylaxis for the reinduction of H4/18 binding but do not inhibit induction by IL‐1α and IL‐1β; similarly, IL‐1α and IL‐1β induce reciprocal tachyphylaxis but do not inhibit TNF or LT. We have used the binding of H4/18 to explore the mechanism of action of TNF. Tumour‐promoting phorbol esters, but not agents which increase cytoplasmic calcium concentrations, were found to induce binding, suggesting a possible involvement of the protein kinase C pathway in the response of HEC to TNF. Cells pretreated for 24 hours with phorbol esters cannot be reinduced to express H4/18 binding by phorbol esters yet retain full responsiveness to TNF. Thus TNF also appears to act on HEC through a pathway independent of protein kinase C activation. Collectively, these effects of TNF and related cytokines may be understood as examples of endothelial cell activation.