Disparate effects of tumor necrosis factor-alpha/cachectin and tumor necrosis factor-beta/lymphotoxin on hematopoietic growth factor production and neutrophil adhesion molecule expression by cultured human endothelial cells.
Tumor necrosis factor-alpha/cachectin (TNF-alpha) and tumor necrosis factor-beta/lymphotoxin (TNF-beta) are inflammatory mediators with similar spectrums of cytotoxic activity against tumors in vitro and in vivo. We compared the effect of purified recombinant human TNF-alpha and TNF-beta on neutrophil adhesion molecule expression and hematopoietic growth factor production by cultured human umbilical vein endothelial cells. Endothelial cells acquired adhesive properties for neutrophils after a 4-hr incubation with as little as 5 U/ml TNF-alpha. TNF-alpha stimulated a dose-dependent increase in endothelial cell adhesiveness for neutrophils, with a maximal effect at 250 U/ml. In contrast, TNF-beta did not enhance endothelial-dependent neutrophil adherence until a concentration of 600 to 1200 U/ml was reached. Endothelial cells cultured for 24 hr with TNF-alpha, 10 to 1,000 U/ml, released hematopoietic colony-stimulating activity. TNF-beta failed to augment growth factor production by endothelial cells at any concentration tested. Inhibitor assays showed that the absence of detectable colony-stimulating activity was not due to direct inhibition of colony growth by TNF-beta or to release of hematopoietic inhibitors by the TNF-beta-stimulated endothelial cells. Purified natural TNF-beta was similar to recombinant TNF-beta in its effect on neutrophil adhesion molecule expression and growth factor production by endothelial cells. These results indicate that the two immunomodulatory proteins TNF-alpha and TNF-beta differ in their effects on a common target tissue. TNF-beta, which retains tumoricidal properties, shows fewer proinflammatory activities on cultured endothelial cells than TNF-alpha in vitro.
D000954:Antigens, Surface / Q000096:biosynthesis*; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules; D002478:Cells, Cultured; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D003603:Cytotoxins / Q000494:pharmacology; D004727:Endothelium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation; D009504:Neutrophils / Q000166:cytology; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha
D000954:Antigens, Surface; D015815:Cell Adhesion Molecules; D003115:Colony-Stimulating Factors; D003603:Cytotoxins; D006023:Glycoproteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha