Tumor necrosis factor-alpha exhibits greater proinflammatory activity than lymphotoxin in vitro.
Tumor necrosis factor-alpha/cachectin (TNF-alpha) and lymphotoxin (LT, TNF-beta) are primarily products of monocytes and lymphocytes, respectively. The proteins are 51% homologous in their primary structure, cause necrosis of Meth A sarcoma in vivo, are toxic to selected tumor cells in vitro, and bind to the same receptor on cells in vitro. However, some recent studies have indicated both qualitative and quantitative differences between recombinant human (rh) LT and rhTNF with respect to inducing human umbilical vein endothelial cell (HEC) adhesiveness for neutrophils and release of hematopoietic growth factor and interleukin-1 (IL-1) from HEC. The rhLT used in these studies was expressed in bacteria and was consequently not glycosylated, whereas natural LT is glycosylated. Therefore, we have compared various preparations of glycosylated and nonglycosylated rhLT with two preparations of rhTNF with respect to their proinflammatory characteristics. We now report that the same LT cDNA, when expressed in mammalian cell line and appropriately glycosylated, is also markedly less potent than rhTNF on a molar basis in inducing endothelial adhesiveness for neutrophils and in directly activating neutrophil adherence to albumin-coated plastic. All recombinant proteins, however, were equipotent on a molar basis in producing cytotoxicity in L929 cells. We conclude that differences in the primary structure of rhTNF and rhLT, rather than alterations induced by prokaryote protein processing, account for the disparate proinflammatory activity in vitro.
Desch
C E
CE
Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond.
Dobrina
A
A
Aggarwal
B B
BB
Harlan
J M
JM
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D008233:Lymphotoxin-alpha / Q000494:pharmacology*; D051379:Mice; D009504:Neutrophils / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha